37232oumal of , Neurosurgety, anid Psychiatri 1993;56:372-381

Nature and incidence of peripheral syndromes in HIV infection J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from

Geraint N Fuller, Jean M Jacobs, Roberto J Guiloff

Abstract who attended hospitals and clinics in the East Fifty four patients with peripheral nerve Riverside area. Patients were excluded if they syndromes were seen during a 15 month had been exposed to neurotoxins (drugs such period in a population of about 1500 HIV as vincrinstine, isoniazid, or thalidomide or infected patients at all stages of the dis- regularly took more than 40 units of alcohol a ease. Distal symmetrical peripheral neu- week) or had other systemic conditions, not ropathies were seen in 38 of the 54 related to HIV, associated with peripheral patients, (11.5% of AIDS patients) and neuropathy (such as diabetes or uraemia) or could be distinguished into two forms. had a family history of . The most common (n = 25) was a painful Patients were classified as having AIDS peripheral neuropathy during AIDS, according to the CDC criteria4; they were which is distinct clinically and pathologi- classified as having AIDS related complex if cally, having axonal atrophy, and is asso- they were HIV positive and had persistent ciated with cytomegalovirus infection at generalised lymphadenopathy, fever, oral other sites. The 13 non-painful neu- hairy leukoplakia, oral candidiasis, herpes ropathies seen were more heterogenous. zoster radiculitis, and foliculitis but lacked Lumbosacral polyradiculopathy associat- AIDS defining opportunistic infections or ed with cytomegalovirus and lymphoma- tumours. At the time of the study the neuro- tous mononeuritis multiplex occurred in toxic nucleoside analogues DDI and DDC fewer than 1% of AIDS patients. Mono- were not being used. neuropathies were seen in 3% of AIDS At the start of the study (September 1988) patients. No patients with acute or 1353 HIV positive patients were being fol- chronic inflammatory demyelinating lowed up at these clinics. A total of 748 had polyradiculoneuropathies were seen. The AIDS related complex and 261 had AIDS (C annual incidence of neuropathies during Dalton, personal communication). By the AIDS related complex stage was less September 1989 there were 1765 HIV posi- than 1%; none were seen in asympto- tive patients, of whom 778 had AIDS related matic HIV seropositive patients. complex and 297 had AIDS. Of the HIV pos- itive patients, 83% were homosexual or bisex- (3 Neurol Neurosurg Psychiatry 1993;56:372-38 1) ual, 4-4% were drug misusers, and 2 5% were

heterosexual and did not misuse drugs. For http://jnnp.bmj.com/ 10% the risk factors were unknown. There A variety of peripheral nerve syndromes have were no haemophilics. Between September been described at different stages of HIV 1988 and 1 September 1989, 105 patients infection, from seroconversion to AIDS. died with AIDS in this population. Most described are case reports or small Patients were assessed with a standardised selected series which do not estimate the inci- neurological examination. The five found to dence. A large prospective study of HIV have bilateral upper motor neuron signs at on October 1, 2021 by guest. Protected copyright. positive patients found that peripheral neuro- presentation of peripheral neuropathy will be pathies were rare', and a cross sectional study considered separately to allow the clinical fea- of 40 hospitalised patients with AIDS found tures of the neuropathy to be studied in isola- Department of that 33% had peripheral neuropathies.2 We tion. The following HIV related and Neurology, report the nature and frequency of Westminster Hospital, peripheral nutritional data were collected in a standard- London nerve syndromes seen during a 15 month ised way: duration of AIDS, previous HIV G N Fuller prospective, population based, referral series related infections (using CDC criteria4), CD4 R J Guiloff from a population of about 1500 HIV posi- count (ACSCAN TM, Becton Dickinson), Department of tive patients3 and discuss the findings in rela- body mass index (weight divided bv height Neuropathology, Institute of Neurology, tion to current classifications of peripheral squared), serum B- 12 concentration (DICO- Queen Square, nerve syndromes. PAC radioimmunoassays; normal range London 210-900 pg/ml), and serum albumin concen- J M Jacobs tration. The same data were collected for the Correspondence to: R J Guiloff, Department of Methods neurologically asymptomatic AIDS controls Neurology, Westminster and PATIENTS and the series of sequential patients wvith Chelsea Hospital, 369 Fulham Road, London Patients were included if they had been AIDS admitted to hospital (see below). SW10 9NH, UK referred to the neurology department with Patients were classified according to the Received 4 Februarv 1992 peripheral nerve syndromes between 1 stage of the disease and the pattern of the and in revised form 19 June 1992. September 1988 and 31 December 1989 peripheral nerve syndrome (distal symmetri- Accepted 6 August 1992. from the population of HIV infected patients cal peripheral neuropathv, mononeuritis mul- Natzure anid itncidenice ofperipheral nerve syndronies in HIV infection 373

tiplex, polyradiculopathy, or mononeuro- STATISTICS pathy). The distal symmetrical peripheral Normally distributed variables were com- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from neuropathies were distinguished as those with pared by using one sample Student's t test. and those without. Pain was defined as Non-normally distributed variables were an unpleasant sensory experience subjectively compared by using the Mann-Whitney U recognised by the patient and mentioned in test. Proportions were compared by using the the history. No formal pain scale was used. two tailed Fisher's exact test. All statistics This distinction is further considered in the were performed with the Statgraphics statisti- discussion. cal package (STSC Plusware, 1987). Standardised electrophysiological studies and pathological studies of the sural nerve were performed using previously described Results methods. Fifty four patients with peripheral nerve syn- dromes were seen. All were male. Thirty eight CONTROL GROUPS had distal symmetrical peripheral neuro- Neurologically asymptomatic AIDS patients- pathies; 25 (66%) of these were painful, 13 Patients with AIDS but without signs or painless. Eleven patients had mononeu- symptoms of peripheral neuropathy were ropathies, three had mononeuritis multiplex, assessed clinically (n = 30) and were studied and two had lumbosacral polyradiculopathy. electrophysiologically (n = 30) and pathologi- Table 1 gives the HIV and nutritional vari- cally (n = 5). Data related to HIV and nutri- ables for the control groups and for the tion were noted as described above. The patients with distal symmetrical peripheral group has previously been described in neuropathies. detail;7 and it provided electrophysiological and pathological control data (see table 4). PAINIFUL PERIPHERAL NEUROPATHIES Patients with AIDS admitted to hospital Twelve of 25 patients with painful peripheral sequentially (n = 30) were assessed separately neuropathies (PPN) were reported on previ- and the standardised HIV related data were ously.8 The variables related to HIV infection collected. This data has been published previ- and nutrition are given in table 1 and the pre- ously.8 Sequential patients, with or without ceding infections in table 2. The duration of neuropathies, were recruited to determine the AIDS, CD4 count, body mass index, albu- frequency of different opportunistic infections min concentration and percentage of patients in patients with AIDS from the population with abnormal vitamin B,2 did not differ from under study, unselected in relation to their those in the control groups. Five patients had neurological symptoms (see tables 1 and 2). clinical evidence of an associated myelopathy. Sudden death controls-The sural from eight patients (mean age 42 (range Clinicalfeatures 21-58) years) without risk factors for HIV Pain was the most prominent symptom, com- infection and without history of peripheral monly described as burning (10/20) or neuropathy, all of whom died suddenly, were intense pins and needles (9/20). Two patients examined morphometrically and used as con- referred to it as frostbite and one as having trols for pathological data. They have been the soles of his feet beaten with bamboo

described previously.57 sticks. Four patients with painful dysaesthesia http://jnnp.bmj.com/ Normal controls-Nerve conduction studies also had shooting to the feet. The pain have been carried out on 23 healthy men age was almost always made worse by contact matched (mean 31-2 (21-45) years) with the (19/20), often by as little as the weight of the neurologically asymptomatic AIDS patients; sheets on the bed. Most patients had to stop the results (see table 4) have been published wearing their normal shoes and usually had to previously.7 resort to slippers. One patient became wheel- on October 1, 2021 by guest. Protected copyright.

Table I HIV infection and nutrition in patients with peripheral neuropathies and controls with AIDS Controls with AIDS Patients wuith Sequential Neurologically Patiehts with PPN admissions asymptomatic OPN (?u = 25) (n = 30) (n = 30) (n = 13) Mean(SD) age (years) 36 (6 5) 40 (9-4) 37 (9-1) 41 (7 3) HIV infection: Median (interquartile range) duration of AIDS 11-0 (3-17) 14-0 (3-23) 11-5 (3-20) 12-5 (3-24) Median (interquartile range) CD4 count (Oil) 4-0 (7-21) 18-5 (10-40) 20-5 (10-68) 12-0 (6-25) Nutritional indicators Mean(SD) body Mass Index 19-3* (2-8) 19 9** (2-1) 17-3 (2-5) (kg/m2; normal range 21-3-29-0) Mean(SD) albumin concentration 34 (5-6) 34 (5 9) 35 (5-4) (g/l; normal range 35-45 g/l) % of patients with abnormal 8-3 24 4 (31) serum B-12 PPN = painful peripheral neuropathy; OPN = other (non-painful) peripheral neuropathy. *p < 0-02 v other (non-painful peripheral neuropathy). **p < 0 005 v other (non-painful peripheral neuropathy). 374 Fuller, Jacobs, Guiloff

Table 2 Percentage ofprior and current infections in patients with painful peripheral neuropathy (PPN), non-painful peripheral neuropathy (OPN) and controls with AIDS. Controls with AIDS J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from Patients with Sequential Neurologically Patients with PPNt admissions asyniptonmatic OPN (n = 22) (n = 30) (n 30) (n = 13) Pneumocystis carinii pneumonia 69 67 70 69 Cytomegalovirus: Any site 78** 37 40 31 Retinitis 46 27 23 8 Gastrointestinal 18 10 20 23 Pneumonitis 23 6 3 8 Kaposi's sarcoma 32 27 27 46 Visceral candidiasis 19 20 23 15 Cryptosporidiosis 0 17 17 15 Toxoplasmosis 6 13 13 0 Lymphoma 6 0 3 0 Cryptococcal meningitis 9 0 3 0 Mycobacterium avium intracellulare infection 4 3 0 31 * tExcludes the last three patients seen (see text). *p <005, **p < 001. Probability of proportion v (Fisher's exact test).

chair bound because of extreme contact pain. two was this volunteered spontaneously. A The pain was limited to the legs in all but two further three noted urinary symptoms; one patients, mostly affecting the feet (n = 17). It had difficulty with micturition and two had was limited to the toes in two patients and to frequency. the soles in one. One patient had low back Distal weakness with wasting of extensor pain at the onset. The symptoms were sym- digitorum brevis was found in five of 20 metrical in all but four patients. patients. In a further patient, distal weakness The onset of pain was subacute, usually developed 10 months after the onset of pain. beginning with stiffness in the toes, later pro- At the first assessment the ankle reflexes were gressing to become painful. Maximum pain normal in 10, impaired in five, and absent in usually occurred within two to four weeks five. There was a progressive loss of ankle (13/20); in one patient the pain reached its reflexes, with the reflex being absent at the peak in less than a week; in another it took final assessment in 14 patients and impaired over two months. The pain usually improved in three. No patient had distal lower limb spontaneously (in eight patients it resolved oedema. completely) but in six patients it persisted Sensory abnormalities were predominantly unchanged. One patient had recurrence of of superficial sensation. All patients had alter- pain followed by further improvement. Some ation of light touch or pinprick (loss of light symptomatic relief was obtained with carba- touch in 12 and pinprick in 15). Subjective extended to the ankle while the loss mazepine in seven patients and changes http://jnnp.bmj.com/ in eight, but both drugs failed to help in one was usually in the toes. In all but three instance. Two patients reported that marijua- patients the changes were limited to the legs. na alleviated the pain. Two patients had In these three the loss in the arms was Kaposi's sarcoma in the feet but it was restricted to the fingertips in two and to the thought unlikely to be the cause of the pain little finger in one. Temperature sensation as neither the site nor the time course of was altered in 15; vibration sense was abnor- the pain matched that of the Kaposi's mal in 15 but only to the level of the toes. sarcoma. Position sense was impaired at the toes in six. on October 1, 2021 by guest. Protected copyright. All patients complained of numbness, In eight, the sensory signs did not alter. In 10 which was again mostly in the feet (17/20), to there were changes: improvement in two, a mid-calf in one patient, only in the toes in deterioration in eight. The change was slight one, and in the soles in another. Three with the exception of those patients who were patients noted numbness in their fingertips. initially assessed within one or two weeks of Paraesthesia was felt in the feet in 13, to mid- the onset of their symptoms. calf in one, in the toes in one, and the finger- The clinical features of patients with tips in two. No patients complained peripheral neuropathies are summarised in spontaneously of weakness. Three patients table 3. The clinical features of the five had observed their toes moving spontaneous- patients who also had signs of a myelopathy ly, an observation confirmed in two. In two at presentation were similar, but in addition patients, mononeuropathies had been the first they had bilateral pyramidal weakness and indication of peripheral nerve dysfunction pathologically brisk reflexes in the arms and (meralgia paraesthetica in one and a probable at the knee. The ankle reflexes were abnormal common peroneal palsy in the other). A fur- in all five at presentation. ther patient had an episode of meralgia Twenty three patients were followed up paraesthetica six months before the onset of until death (median 7 months, range 1-21 his pain. Half the patients had noted that they months); two were alive at review at 10 and became impotent at the onset of pain; in only 14 months. Natuire atid incidence ofperipheral nerve syndromes in HIV infection 375

Table 3 Clinicalfeatures ofpatienits with paitnful (PPN\) latency. The F waves in extensor digitorum and other peripheral nieuropathies (OPN) without brevis were not recordable in 46% of patients evidenice of myelopathy, values are nunubers ofpatietnts with PPN, but when recordable the latency J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from PPN OPAN was no different from that in controls. The (ni = 20) Ou = 9) patients with myelopathy were comparable ,Syvnptomls electrophysiologically to those without. Pain: Burning 10 Dvsaesthesiae 9 Pathology Shooting 4 Frostbite 2 Pathological study of eight sural nerves Associations: revealed no inflammation with degenerating Numbness 20 8 fibres and a reduced myelinated fibre density Paraesthesiae 17 7 Weakness 0 5 (mean(SD) 4396 (931); fig 1). This is lower Moving toes 3 0 than the myelinated fibre density in the five Back pain 0 asymptomatic AIDS patients Onset: neurologically 0-2 Weeks 13 0 (5 454 (631); p = 0 06). The neurologically 2-4 Weeks 13 0 AIDS patients had a mean 4-8 Weeks 4 asymptomatic ) 8 Weeks 0 8 reduction in fibre density of 30 5% compared Site: to the sudden death controls (mean(SD) fibre Toes 2 0 7 845 Axonal atrophy was Feet 18 9 density (1414)). Fingers 3 5 found in the myelinated fibres in nerves from Signs all eight patients with painful peripheral neu- Wasting (distal) 5 4 ropathy studied qualitatively (figs 1 and 2) Weakness (distal) 5 6 and in the four of them studied quantita- Ankle reflex: Normal 10 2 tively.6 There were clusters of Schwann cell Impaired 5 2 processes with a few unmyelinated axons sug- Absent 5 5 gesting unmyelinated axon loss (mean(SD) Sensory: Cotton wool: density 22 280 (3022)). This was not signifi- Altered 20 8 cantly different from density in the five (neu- Lost 13 4 Pinprick: rologically asymptomatic AIDS patients (22 Altered 20 8 006 (2357)). The unmyelinated fibre densi- Lost 14 3 Vibration sense 15 7 ties were lower than in the sudden death con- Proprioception 6 2 trols (30 900 (7117)) but this did not reach Temperature 15 8 statistical significance. These results have Upper level of sensory signs: Toe 2 I been reported in detail elsewhere.6 Midfoot 4 0 Ankle 1 0 5 Midshin or above 4 2 Associations Fingers 3 5 A study of the first 12 of these patients with Progress PPN a with Pain: revealed temporal relation Resolved 6 cytomegalovirus infection with 75% having Improved 9 previous or current cytomegalovirus infection Persisted 5 Deteriorated 0 compared to 37% in the control group of Ankle reflex: sequential admissions who had AIDS of simi- Reduced 6 1 lar severity, as assessed by duration of infec- Lost 9 0 http://jnnp.bmj.com/ < Sensory loss: tion and CD4 counts (table 1; p 0.05).8 Improved 2 1 This association held when all 25 patients Stable 10 4 Deteriorated 8 4 were considered; the rate then was 78% or 80%. In the 13 further cases, eight had clear evidence of cytomegalovirus infection (retini- tis in three, colitis in two, pneumonitis in two, and oesophagitis in one); in three treat- Cerebrospinalfluid. ment for cytomegalovirus infection had been on October 1, 2021 by guest. Protected copyright. Cerebrospinal fluid was studied in 12 started, partly on the basis of PPN. Of these patients. All had five or less white cells, the last three patients, two had PCP negative protein concentration was raised in seven pneumonia with CMV and no other (mean 0-71 (range 0-2-1-3) g/l), in four to pathogens found in induced sputum, and one over 1 g/l. (who declined biopsy) had a herpes simplex virus negative perianal ulcer. Thus, the rate of Electrophysiology cytomegalovirus infection was 80% in all Table 4 shows that the reduction in the sen- cases and 78% if the last three were excluded. sory nerve action potentials was greater in the The rate of other infections did not differ legs than in the arms. Sensory conduction from a control group of sequential admissions velocities were significantly lower than in nor from that found in neurologically asymp- neurologically asymptomatic AIDS patients. tomatic controls (table 2).8 Motor action potentials in the did The serum B- 12 concentration in patients not differ from those in this control group. with PPN did not differ from that in the neuro- The common peroneal compound muscle logically asymptomatic AIDS patients who action potential was significantly smaller. were at a similar stage in the disease. Only Distal motor latencies of the common per- 8-3% had abnormal concentrations of B2, and oneal were slightly prolonged. There was no the albumin concentrations were similar to the difference in the ulnar nerve distal motor neurologically asymptomatic group (table 1). 376 Fuller, J7acobs, Guiloff

Table 4 Nerve conduction studies in peripheral neuropathies in AIDS patients and control groups. Values are means (SD) or [nfedian (iinterquartile range)] J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from Patients wvith peripheral nieuiropathy Coutrolst Neutrologicall/v PPN (u = 23) OPN (ui = 13) asy,mptoilatic AIDS(ui = ?0) Norial (i = 2.?) Sensory conduction: Sensory nerve action potential (, V) Ulnar 9 4 (4 5)* 6-5 (3.5)** 12-0 (4 2) 15 4 (6-0) Median 12 2 (6 2)* 11-3 (6 4)* 17 5 (6 6) 22-1 (8 4) Sural [1-0 (0-4)]* [0-8 (0-2 6)]** 9-9 (3-5) 15.0 (4 5) Motor conduction: Compound muscle action potential (mV) Ulnar 9 4 (3-9) 10-0 (2 4) 10 5 (2 6) 14 4 (298) Common peroneal [1 4 (0 6-2 0)]** [ 0 7 (0-1l5)]** 3 7 (2-0) 5-7 (2 8) Distal motor latency (ms) Ulnar 3-1 (0 8) 3-2 (0-7)* 2 8 (0 7) 2-7 (0 4) Common peroneal 5-4(12)* 6 3 (1l8)* 4-6 (0 7) 45 (0-8) Motor conduction velocity (m/s) Ulnar 52 2 (8 0)** 51 3 (4 8)** 57-3 (4 9) 60 2 (4 7) Common peroneal 36 6 (5-1)** 34-2 (4.7)** 43.9 (5*0 49 8 (4 8) F waves (m/s) Abductor digiti minimi 68-0 (7-0) 67 3 (6 1) 70 2 (5 5) 73.9 (4 9) Extensor digitorum brevis 35-2 (5 5) 30-2 (2.5)** 36 6 (3 9) 42 3 (3 8) *p = 0-05-0-01, **p < 0-01; comparison with neurologically asymptomatic controls. tA comparison of normal controls with ncu- rologically asymptomatic AIDS patients has been published. tF-waves corrected according to formula: height (F-wave latency - M-wave latency - 1). PPN = painful peripheral neuropathy; OPN = other (non-painful) peripheral neuropathies. SAP = SensorV nerve action potential, CMAP = Compound muscle action potential, DML = Distal motor latency, MCV = Motor conduction velocity, ADM = Abductor digiti minimi, EDB = Extensor digitorum brevis

OTHER PERIPHERAL NEUROPATHIES toms or signs in both arms and legs; in four The characteristics of the 13 patients with the symptoms were limited to the legs. Three non-painful neuropathies (OPN) are given in patients had clinical evidence of super-added table 1; the preceeding infections are given in mononeuropathies. Eight of the patients table 2. The severity of AIDS in these neu- complained of numbness, seven of paraesthe- ropathies was not significantly different from sia, and five of weakness. The onset of the either of the control groups, nor from patients neuropathy was insidious, in most patients with painful neuropathies. coming on over two months, in one possibly over years. Focal wasting distally was found Clinicalfeatures in four patients; in six there was distal weak- Six patients had sensorimotor neuropathies, ness. Ankle reflexes were absent in five four had- additional bilateral upper motor patients, impaired in two, normal in two. neuron signs, and three had purely sensory Superficial sensation was altered in all but neuropathies. Five of the patients had symp- one patient, being limited to the toes in one,

Figure I One micron araldite sections ofsural http://jnnp.bmj.com/ nerve x 470. (a) Froni a patient with painful peripheral neuropathy: there is a reduced density offibres; nmanyfibres are atrophic and a few are degenerating (arrows); (b) front a patient with non-painful peripheral neuropathy: thefibre on October 1, 2021 by guest. Protected copyright. denlsity, is redulced anid degeneratingfibres are seen (arrozvs); (c) control nerve.

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* A.£2 Nature and incidenice ofperipheral nierve synidronmes in HIV infectiotn 377 Pathology have been reported in Pathological findings J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from detail elsewhere.6 There was evidence of myelinated fibre loss with degenerating fibres (fig 1) but no evidence of axonal atrophy in three sural nerves studied quantitatively.6 Mean (SD) myelinated fibre density was 4796 (414) and unmyelinated fibre density was 22 475 (5043). None of the five sural nerves of neurologi- cally asymptomatic AIDS patients with sub- clinical neuropathy7 showed axonal atrophy qualitatively, nor was it found in one nerve studied quantitatively.6 Associations Two associations were noted. Firstly, the body mass index was significantly lower than in either the asymptomatic AIDS controls (p < 0 005) or in patients with painful periph- eral neuropathy (p < 0 02) (table 1). Secondly, Mycobacterium avium intracellulare infection was more common than in a group of sequential AIDS controls (4/13 v 1/30;8 p < 0 03). The rate of other infections did not Figure 2 Electron micrograph ofsural ierve from patient with paitnful peripheral differ from that in the neurologically asymp- nieuropathy, showing three atrophic nmyelinatedfibres with axons that are snmall relative to myelin sheath thickness. Bar = 5 lin. tomatic or sequential admission AIDS control groups (table 2). A total of 31% of these patients had abnormal concentrations of B,2, the foot in five, and the knees in two. Sensczry a slightly higher rate, though not significantly loss in the fingers was found in five patienLts; so, than in the neurologically asymptomatic posterior column loss was found in sevwen. AIDS group. The symptoms and signs of the neuropat:hy were progressive in four patients, static in MONONEURITIS MULTIPLEX four, and apparently improved in one. T'wo One patient aged 57 with AIDS related com- patients had pes cavus. Four patients with plex presented with a rapidly progressive myelopathy and neuropathy had similar clini- monoplegia associated with pneumococcal cal pictures. pneumonia. He was positive for hepatitis B Twelve patients were followed until deeath surface antigen. He deteriorated rapidly and (median 8 months, range 1-17 months); one at necropsy a large vessel vasculitis of the was reviewed nine months after onset of femoral nerve was found. symptoms. Two patients were seen with mononeuritis

multiplex related to lymphoma. One aged 41 http://jnnp.bmj.com/ Electrophysiology presented with fevers and weight loss together Table 4 summarises the electrophysiolc)gy with a right femoral neuropathy. Hepatic findings. Sensory nerve action potentials were ultrasound showed multiple lesions. He died reduced, more in the legs than in the arnns. shortly after investigation and was found to Sensory conduction velocities were sign ifi- have a non-Hodgkin B cell lymphoma in cantly reduced when compared with those in nodes and liver. Lymphoma was found infil- asymptomatic AIDS patierits. trating his femoral nerve (fig 3). Another

neurologically on October 1, 2021 by guest. Protected copyright. Motor action potentials in the ulnar nerve ( not differ from those in this control groi The common peroneal compound mus action potential was significantly small Distal motor latencies of the common p oneal were slightly prolonged. There was difference in the ulnar nerve distal mo latency. The F waves in extensor digitori brevis were not recordable in 46% of 1 patients, although when they were recorda the latency was no different from that in control group. The patients with myelopa were comparable electrophysiologically those without. Cerebrospinalfluid Cerebrospinal fluid was acellular in patients studied. Four out of five patients I Figure 3 Paraffin section (x 140) offemoral nerve raised concentrations of protein (mean 0 showinig infiltration of the endoneuriumi by colunins of g/l, range 0'4-1 7 g/l). lyniphonia cells. 378 Fuller, Jracobs, Guiloff

patient, aged 34, presented with multiple cra- through the study can be obtained and this nial nerve palsies and a cervical can be used to estimate the 15 month inci- and was found to have lymphomatous menin- dence of the various syndromes (table 5). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from gitis. Painful peripheral neuropathy was the most common, occurring in 7 5% of AIDS ISOLATED MONONEUROPATHIES patients; non-painful peripheral neuropathies Three patients with isolated mononeu- were seen in 4%. Mononeuropathy occurred ropathies had AIDS related complex and in 3% of AIDS patients, and mononeuritis eight had AIDS. Their mean (SD) age was multiplex and a lumbosacral polyradiculopa- 41-1 (6-7) years. The patients with AIDS thy were each seen in 06%. Neuropathies related complex had a median CD4 count of during the AIDS related complex stage 160/,ul and a mean body mass index of 26&6. occurred in fewer than 1% of patients. Those with AIDS had a median CD4 count These estimates contain several possible of 55/,il and a body mass index of 21-6. The sources of inaccuracy. Firstly, the patients nerve most commonly affected was the lateral may not have been referred to the neurology cutaneous nerve of the (n = 5), fol- service. Secondly, the population was chang- lowed by the common peroneal (n = 3) and ing and patients may have sought treatment median (n = 3) nerves. The neuropathies pre- elsewhere. Thirdly, patients were excluded sented usually either during or after the when they had other potential causes for neu- patients had been admitted to hospital (7/11) ropathy, even though these causes may not for a variety of infections or tumours. In most have produced the relevant neuropathy. no local cause was found. In one patient a These exclusions prevent this study from meralgia paraesthetica occurred at the same assessing whether pre-existing neuropathy time and side as inguinal lymphadenopathy predisposes to the development of PPN. due to lymphoma; it resolved with treatment In table 5 the incidence and relative rates of the lymphoma. In a further seven patients of different patterns of neuropathies are com- the mononeuropathy resolved spontaneously. pared with those of other unselected series, In three (one with meralgia paraesthetica, one including case series, prevalence studies, and common peroneal and one median), the a point prevalence study. In all studies, distal symptoms persisted. symmetrical peripheral neuropathies were the Results of electrophysiological studies in most common and account for some 90% of nerves other than those affected clinically did all neuropathies in AIDS. In early series they not differ from those in neurologically asymp- were estimated to affect 2-5% of AIDS tomatic AIDS patients. patients.'01' In a study comparable to ours from Baltimore,'2 13% of AIDS patients had POLYRADICULOPATHY distal symmetrical peripheral neuropathies. In Two patients with lumbosacral polyradicu- our series, lumbosacral polyradiculopathy and lopathy have been reported in detail else- mononeuritis multiplex each were found in where.9 fewer than 1% of patients with AIDS and AIDS related complex. Other researchers have described a syn- Discussion drome similar to painful peripheral neuropa-

We have described the range of peripheral thy, usually grouped together with http://jnnp.bmj.com/ nerve syndromes seen in a 15 month period non-painful neuropathies, as "predominantly in a relatively stable outpatient population of sensory neuropathy," "sensory motor HIV positive patients at various stages of their neuropathy," "distal symmetrical polyneu- disease. As the population was known at two ropathy," or "painful neuropathy".'2-'5 When points, an estimate of the population halfway the clinical features were similar to those on October 1, 2021 by guest. Protected copyright. Table 5 Series ofperipheral nteuropathies ofsix or nmore cases

Aiuthorvear Ceitre Population DSPN CIDP AIDP AlAI LS PR AIX Snider et al, 1983"' New York 160 AIDS 8 (5'S,) Levy e al, 1985" San 318 AIDS or 5 (2'S) Francisco ARC 2 9 (3"/,) Guiloff et al, 1988' London 122 AIDS 4 (3'i,) 1 (O 8'!,) 1 (0 8"o) Cornblath and Baltimore Est 200 AIDS 26 (13'S,) 1 (05'S>) McArthur, 19882 ? ARC 1 ? HIV+ 7 3 **Miller et al, 1988' San NS 18 10 2 3 Francisco tSo et at, 1988 San 40 AIDS 13 (33%h) Francisco Lange et al, 1988' 5 New York NS AIDS HIV + ***Leger et at, 19892 Paris NS AIDS 15 2 1 1 ***Chaunu et al, 198921 ARC 8 3 HIV+ 5 This series London 331 AIDS 38 (1 1 5'S.) 2 (0 6N/,) 2 (0(6'"0) 8 (3 !0"o) 763 ARC 1 (O "X.) 3 (0)4"'o) 565 HIV + DSPN = Distal symmetrical peripheral neuropathy. CIDP = Chronic inflammatory demyelinated . AIDP = Acute inflammatory demyelinating polyradiculoneuropathy. MM = Mononeuritis multiplex. LSPR = Lumbosacral polyradicu- lopathy. MN = Mononeuropathies. NS = not stated. ARC = AIDS related complex. Percentages of given populations are in brackets. **not classified by disease stage. ***2 overlapping series combined. tLimited to hospitalised patients. Nature and incidence ofperipheral tnerve syndronmes itn HIV infection3379

described here, pain was reported in about pathology. This is supported by the F wave

60% of patients, in all limited to the feet. velocities not differing from those in our neu- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from Complaints of weakness are uncommon. rologically asymptomatic AIDS controls. Mild distal weakness was found in some and Axonal loss was found in all our cases of dis- the ankle reflexes were usually lost or tal symmetrical peripheral neuropathy and impaired. Sensory loss was usually mild, most has been consistently reported by others.'3 '1 often affecting vibration sense and pinprick 20-21 Myelinated fibre densities were reduced and often associated with contact dysaesthe- to a similar degree in this and other studies.' sia. ' Previous reports have noted that the 23 The myelinated fibre density in patients pain has remained prominent,'5 although the with PPN was 20% lower than that in neuro- neuropathy has progressed.'2 In 75% of our logically asymptomatic controls but no differ- patients with painful peripheral neuropathy ent from that in patients with OPN. The the pain improved or resolved and patients density of unmyelinated axons was the same required less analgesia or pain modulating as in the asymptomatic controls (22 260 v 22 agents such as tricyclics or carbamazepine. 016). The unmyelinated fibre density and the The sensory loss remained stable or improved unmyelinated axon density of the patients in 60%, although there was a progressive loss with non-painful peripheral neuropathies of ankle reflexes. Several possible explana- were similar to those of patients with painful tions might account for these different neuropathies. descriptions: the entities may differ in some The only morphological finding that distin- fashion; patients who improve tend to be lost guished patients with a painful peripheral to follow up and this may eschew some series neuropathy from those with other peripheral with limited follow up; and the treatment neuropathies and the neurologically asympto- with anti-cytomegalovirus drugs may alter the matic AIDS controls was axonal atrophy. clinical course of the syndrome. Qualitatively, this was found in all eight sural Defining painful peripheral neuropathy on nerves of patients with painful neuropathies the basis of a single subjective clinical symp- but not in eight nerves of patients with non- tom poses several difficulties. Firstly, individ- painful neuropathies. Quantitatively, it was uals' pain thresholds vary. Secondly, in the seen in all four patients with painful neu- setting of HIV disease, central nervous system ropathies studied but in none of the three disorders such as myelopathy and patients with non-painful distal symmetrical encephalopathy may modulate the pain. neuropathies nor in any neurologically Thirdly, the pain might result from more asymptomatic AIDS patients., A two tailed than one peripheral nerve pathology in AIDS. Fisher's exact test on these data rejects the In this study, as in our earlier report,8 null hypothesis of independence between active cytomegalovirus infection was found in PPN and axonal atrophy (p < 0.03).6 There 80% of patients with painful peripheral neu- was no concomitant atrophy of unmyelinated ropathy as compared to 37% of sequential axons.6 unselected controls who were at a similar These findings can be interpreted in sever- stage of the disease and who were assessed in al ways. Firstly, it can be speculated that the the same way as patients with neuropathy. subclinical peripheral neuropathy found in This should have removed any diagnostic bias neurologically asymptomatic AIDS,7 the in identifying cytomegalovirus. The virus is other non-painful neuropathies, and the http://jnnp.bmj.com/ known to be an important pathogen in AIDS painful peripheral neuropathy in AIDS repre- related lumbosacral polyradiculopathy'6 and sent different points in a continuous spec- in a multifocal sensory motor neuropathy trum. The significantly longer duration of associated with AIDS.'@ On the basis of the OPN than PPN at presentation (table 3) is clinical syndrome, we suggested that the pain against the idea that a non-painful neuropa- in painful peripheral neuropathy may be thy progresses to a point when it becomes

related to a dorsal root ganglionitis,8 and, painful. Alternatively, the painful and the on October 1, 2021 by guest. Protected copyright. indeed, several case reports have found a dor- non-painful peripheral neuropathies may rep- sal root ganglionitis at necropsy.'8I" resent distinct entities which occur in the set- The electrophysiological findings in this ting of a non-specific "axonal. loss of chronic series of patients with distal symmetrical disorders." Evidence of this loss in our study peripheral neuropathy mirrored those from on AIDS related subclinical peripheral neu- previous studies.""12' Sensory action poten- ropathy,7 the relatively stereotyped clinical tials were considerably reduced, especially in presentation of PPN, and the findings of the legs, with a mild reduction of motor con- associated axonal atrophy and CMV infection duction velocities and compound muscle in PPN would all point to PPN as a distinct action potentials. The F waves have been entity rather than as part of a continuum and reported as being prolonged,'5 although the raise the question as to whether it should rep- comparison was with normal controls rather resent a subdivision in DSPN.24 than asymptomatic AIDS patients. Using The non-painful distal symmetrical periph- such AIDS patients as controls, we found no eral neuropathies reported here seemed to be difference. The findings were similar in more heterogeneous than PPN and two painful and other peripheral neuropathies and patients had pes cavus, suggesting an inherit- consistent with axonopathy. The velocities ed neuropathy despite the lack of a family his- were reduced but to a lesser degree than the tory. In addition, this group had a amplitude of sensory motor action potentials, significantly lower body mass index, suggest- suggesting that demyelination is not a major ing a possible role for nutritional factors. 380 Fuller, _tacobs, Guiloff

These patients also had an increased inci- often involved at entrapment sites, particular-

dence of Mycobacteriuni avium intracellulare ly in patients who have lost weight.36 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.4.372 on 1 April 1993. Downloaded from infection, suggesting a possible role for this Distal symmetrical peripheral neuropathies agent, which has been found in peripheral account for 90% of neuropathies seen in nerve.23 Vitamin B, was found to be abnor- AIDS. The aetiopathogenesis of these syn- mal in 31% of these patients compared with dromes is currently poorly understood. The 24% of the neurologically asymptomatic con- form of painful peripheral neuropathy seen in trols, but this difference did not reach signifi- the AIDS patients described here seems to be cance. These associations must be treated a distinct clinical entity and may have a spe- with caution in the context of multiple statis- cific aetiopathogenesis. Further detailed tical comparisons made between the two pathological studies of these patients are groups. needed. Chronic inflammatory demyelinating was in two We thank Drs B G Gazzard, A Lawrence, and D Hawkins for polyradiculopathy reported only allowing us to study patients under their care, Dr J N patients with AIDS in any series (table 5). Harcourt-Webster for access to postmortem material, and cases have been in Miss J Roberts for secretarial assistance. GNF was an MRC Eighteen reported patients research training fellow; this work formed part of an MD the- with AIDS related complex or asymptomatic sis submitted to the University of London. We received finan- one A cial support from the Special Trustees of Westminster and HIV patients, nearly half from centre.26 Roehampton Hospitals. further 10 were reported from another centre, but the disease stage was not specified.'4 We saw no cases in over a thousand patients dur- 1 McArthur JC, Cohen BA, Selnes OA, Kumar AJ, Cooper a 15 month No cases were K, McArthur JH, et al. Low prevalence of neurological ing period. report- and neuropsychological abnormalities in otherwise ed in a point prevalence study of HIV positive healthy HIV-1-infected individuals: results from the Chronic multicenter AIDS cohort study. Ann Neurol men.' inflammatory demyelating 1989;26:601-1 1. polyradiculopathy during the AIDS, AIDS 2 So YT, Holtzman DM, Abrams DI, Olney RK. Peripheral related complex, and HIV seropositivity neuropathy associated with acquired immunodeficiency syndrome. Prevalance and clinical features from a popu- stages must therefore be recognised as rare. lation-based survey. Arch Neurol 1988;45:945-8. The Guillain-Barre syndrome is rare; only 3 Fuller GN. The peripheral nervous system in HIV infec- tion: a clinical, electrophysiological and pathological four patients were reported in non-selective study [dissertation]. London: University of London, studies There are case 1990. population (table 5). 4 Centers for Disease Control. Revision of the CDC surveil- reports of acute inflammatory demyelinating lance case definition for acquired immunodeficiency polyradiculopathy (AIDP) after seroconver- syndrome. MMWR 1987;36:1-15S. 5 Jacobs JM, Love S. Qualitative and quantitative morphol- sion for HIV27 28 as for other types of infec- ogy of human sural nerve at different ages. Brain tion.2' In a selective series from Zimbabwe, 1985;108:897-924. 6 Fuller GN, Jacobs JM, Guiloff RJ. Axonal atrophy in the 59% of 29 consecutive patients with AIDP painful peripheral neuropathy in AIDS. Acta were found to be HIV positive,30 but serocon- Neuropathologica 1990;81: 198-203. 7 Fuller GN, Jacobs JM, Guiloff RJ. Subclinical peripheral version and asymptomatic HIV positivity nerve involvement in AIDS: an electrophysiological and were not distinguished. The expected rate of pathological study. . Neurol Neurosurg Psychiatry 1991;54:318-24. co-occurrence of AIDP in asymptomatic HIV 8 Fuller GN, Jacobs JM, Guiloff RJ. Association of painful seropositivity by chance is 5-30 cases a year peripheral neuropathy in AIDS with cytomegalovirus infection. Lancet 1989;ii:937-41. (1-2/100 000 population per year)3' in an 9 Fuller GN, Gill SK, Guiloff RJ, Kapoor R, Lucas SB, estimated population of 0 5-1-5 million.32 A Sinclair E, et al. Ganciclovir for lumbosacral polyradicu- in AIDS. 1990;335:48-9.

lopathy Latncet http://jnnp.bmj.com/ definite association between AIDP and 10 Snider WD, Simpson DM, Nielsen S, Gold JW, Metroka asymptomatic HIV seropositivity rather than CE, Posner JB. Neurological complications of the acquired immune deficiency syndrome: analysis of 50 seroconversion must wait for definitive confir- patients. Anal Neurol 1983;14:403-18. mation. The chronic condition is much rarer 11 Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired immunodeficiency syn- than the acute form but accurate incidence drome (AIDS): experience at UCSF and review of the figures are not available; it may therefore be literature. J Neurosurg 1985;62:475-95. 12 Cornblath DR, McArthur JC. Predominantly sensory assumed that the association with HIV neuropathy in patients with AIDS and AIDS-related is real. complex. Neurology 1988;38:794-6.

seropositivity on October 1, 2021 by guest. Protected copyright. was also a rare 13 Bailey RO, Baltch AL, Venkatesh R, Singh JK, Bishop Mononeuritis multiplex MB. Sensory motor neuropathy associated with AIDS. pattern of peripheral nerve involvement in Neurology 1988;38:886-91. our to 14 Miller RG, Parry GJ, Pfaeffl W, Lang W, Lippert R, study, secondary lymphoma during Kiprov D. The spectrum of peripheral neuropathy asso- AIDS and vasculitis during AIDS related ciated with ARC and AIDS. Muscle anid Nerve Infiltration of the nerve 1988;1 1:857-63. complex. peripheral 15 Lange DJ, Britton CB, Younger DS, Hays AP. The neu- by lymphoma is well recognised in HIV nega- romuscular manifestations of human immunodeficiency in one virus infections. Arch Neurol 1988;45: 1084-8. tive lymphomas and retrospective 16 Miller RG, Storey JR, Greco CM. Ganciclovir in the pathological series was found in 40% of 145 treatment of progressive AIDS-related polyradiculopa- It has been thy. Neurology 1990;40:569-74. cases of lymphoma.33 reported 17 Said G, Lacroix C, Chemouilli P, Goulon-Goeau C, sporadically in AIDS.34 Roullet E, Penaud D, et al. Cytomegalovirus neuropathy The most isolated in acquired immunodeficiency syndrome: a clinical and frequent mononeuropa- pathological study. Ainn Neurol 1991 ;29: 139-46. thy was that involving the lateral cutaneous 18 Robert ME, Geraghty JJ, Miles SA, Cornford ME, Vinters nerve of the This is common HV. Severe neuropathy in a patient with acquired thigh. syndrome immune deficiency syndrome (AIDS). Evidence for in men in their 30s and 40s, and cases are widespread cytomegalovirus infection of peripheral often identified on direct nerve and human immunodeficiency virus-like only questioning.33 immunoreactivity of anterior horn cells. Acta This suggests that this presentation may have Neuropathologica 1989;79:255-61. been a reflection of awareness of 19 Budzilovich GN, Avitabile A, Niedt G, Aleksic SN, heightened Rosenblum MK. Polyradiculopathy and sensory gan- physical symptoms in patients with AIDS glionitis due to cytomegalovirus in acquired immune related and AIDS. The other mono- deficiency syndrome (AIDS). Progress in Aids Pathology complex 1989;1: 143-57. neuropathies seen affected nerves that are 20 Berger JR, Sheremata WA, Resnick L, Atherton S, Natuire and inicidence ofperipheral tnerve synidronmes in HIV inifection 381

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