paravertebral muscles disease cervical · keywords: paravertebral muscles; cervical spine dis-ease;...

J7ournal ofNeurology, Neurosurgery, and Psychiatry 1996;61:461-465

Paravertebral muscles in disease of the cervicalspine

S B Wharton, K K Chan, J D Pickard, J R Anderson

Department ofHistopathologyS B WhartonK K ChanJ R AndersonDepartment ofNeurosurgery,AddenbrookesHospital, CambridgeCB2 2QQ, UKJ D PickardCorrespondence to:Dr S B Wharton,Department ofHistopathology,Addenbrookes Hospital,Hill's Road, CambridgeCB2 2QQ, UK.Received 5 March 1996and in final revised form5 July 1996Accepted 19 July 1996

AbstractObjectives-Cervical spine disorders arecommon in the older population. Theparavertebral muscles are essential to thesupport and stabilisation of the cervicalspine but have been little studied. Theaim was to determine whether pathologi-cal changes develop in these muscles inpatients with severe cervical spine dis-ease, which, if present, might contributeto the pathogenesis and symptomatologyof their disorder.Methods-Open biopsies of superficialand deep paravertebral muscles wereobtained during the course of surgicalprocedures to alleviate cervical myelopa-thy. Most of these patients had cervicalspondylosis or rheumatoid arthritisinvolving the cervical spine. The biopsieswere compared with muscle obtained atnecropsy from patients without a historyof cervical spine or neuromuscular disor-der.Results-Muscle from both the study andcontrol groups showed a similar range andseverity of abnormalities. In severalpatients, grouped fibre atrophy suggestedchronic partial denervation. Most biopsiesshowed type 1 fibre predominance andselective type 2 fibre atrophy. Ragged redfibres were a frequent finding and electronmicroscopy disclosed accumulations ofmitochondria, a small proportion ofwhichcontained rounded, or longitudinally ori-ented, single osmiophilic inclusions.Fibres containing core-like areas werealso frequent. These pathological featureswere seen with increasing severity and fre-quency with increasing age.Conclusions-The paravertebral cervicalmuscles develop pathological abnormali-ties with increasing age with both neuro-genic and myopathic features, thepathogenesis of which is probably multi-factorial. Such a muscle disorder would beexpected to be accompanied by finctionalimpairment which may contribute to thedevelopment and symptomatology of cer-vical spine disease with increasing age.

(7 Neurol Neurosurg Psychiatry 1996;61:461-465)

Keywords: paravertebral muscles; cervical spine dis-ease; age related myopathy

Diseases of the cervical and lumbar spine are acommon cause of symptoms and loss of work-

ing days, particularly in people over the age of50. In a small proportion of patients the dis-ease is sufficiently severe that neurologicalabnormalities develop.' The spine is amenableto several imaging modalities including myel-ography, CT, MRI, and discography,23 butthe supporting soft tissues, in particular theparavertebral muscles, have been little studied.Inflammatory or degenerative diseases ofjoints and ligaments are the chief causes ofvertebral instability, but the role of the muscu-lature in the support of the spine is revealed inpatients with Duchenne dystrophy and spinalmuscular atrophy, who develop severe spinaldeformities at a young age.46 Furthermore, inpatients with spinal disease, attention has beenfocused on the importance of the state of thesupporting musculature by studies showingthe beneficial effects of exercise in patientswith spinal disease.78

This study was undertaken to determinewhether appreciable pathological changeswere present in the paravertebral muscles ofpatients with severe cervical spine disease.Such changes, if present, whether arising sec-ondary to the disease of the spine, or primarilyas a result of aging, might contribute to thepathogenesis and symptomatology of disordersof the cervical spine. We have studied the par-avertebral muscles in patients with cervicalspine disease of sufficient severity to requiresurgery. As a control group we have studied anunselected necropsy population with no his-tory of cervical spine disease or of neuromus-cular disorders.

Patients and methodsThe study group comprised 15 patients (11women, four men) with a mean age of 66(range 45 to 81) years. All of these patientswere operated on because of severe cervicalspine disease with neurological and radiologi-cal abnormalities. The underlying diseaseprocess in most patients was either rheuma-toid arthritis (eight patients) or cervicalspondylosis (five patients). One patient wasoperated on for a post-traumatic C4/5 spondy-lolisthesis and one patient for cervical spinedestabilisation due to a solitary metastasis(adenocarcinoma). In most patients the focusof disease was in the mid-cervical region (C3to C6). In two patients with degenerative dis-ease the focus of disease was in the upper cer-vical spine (atlantoaxial and C2/3).The control group comprised an unselected

necropsy population of 23 patients (ninewomen, 14 men) with a mean age of 67 (range

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42Wharton, Chan, Pickard, Anderson

LZ Control ResultsDenervation _ Std Muscle biopsies from both the study and con-

- Study trol groups showed a high prevalence of patho-Necrosis logical abnormalities. The features described

below were seen in both groups with a similarCore-targetoid prevalence and severity (fig 1). Most patients

fibres showed predominance of type 1 fibres.Selective type 2 fibre atrophy, assessed subjec-

3ged red fibres tively, was found in 60%-70% of patients andwas, in some patients, very severe. Evidence ofdenervation, in the form of grouped atrophy

Type 2 atrophy and angular atrophic fibres, was seen in four-__ and two patients in the study and control

Type 1 X groups respectively.predominanc Ragged red fibres were seen in 60%-70% of

patients in both groups (Fig 2A). These fibres0 20 40 60 80 100 showed an excess of lipid and stained intensely

% Patients with NADH-TR. Several patients showedre 1 Nature andfrequency (% patients) ofpathologicalfeatures found in the fibres with a negative cytochrome oxidasedsies from the study and control groups. reaction, particularly when many ragged red

fibres were present. Some of the ragged redfibres were themselves negative forcytochrome oxidase activity (fig 2B), althoughothers had a positive rim.

19 to 99) years. Deaths were mostly related to Core-targetoid fibres were seen in 40%-vascular disease or malignancy, with sudden 50% of patients in both groups, consisting oftraumatic death accounting for some of the rounded areas of absent reactivity on histo-younger patients. None of the patients had a chemical preparations for NADH-TR (fighistory of cervical spine disease or neuromus- 2C). In most of these patients they were pre-cular disease, and there were no patients with sent in 10% to 20% of the fibres, ranging fromrheumatoid arthritis. less than 5% to about 30% of fibres. In one

In the study group, biopsies were taken at patient in the study group, nemaline rods werethe approximate level of the disease (mostly seen. Scattered necrotic fibres were seen inmid-cervical) from the semispinalis capitis 40%-50% of patients; these were not associ-(superficial) and semispinalis cervicis (deep) ated with inflammation. Inflammation, whenmuscles at the time of surgery to carry out cer- present (in 27% of the study group and 13%vical fusion. In the necropsy population, biop- of controls), was mild and focal, consisting ofsies were taken from the same group of a few chronic inflammatory cells in themuscles at roughly the mid-cervical level endomysium which did not invade musclewithin 48 hours of death (usually within 24 fibres.hours). Biopsies were snap frozen in isopen-tane and stored at -70°C until use. Frozensections were cut in a cryostat and stained withhaematoxylin and eosin, modified Gomori'strichrome, periodic acid Schiff, and oil red 0.

Histochemistry was performed for NADHtetrazolium reductase (NADH-TR), cyto-chrome oxidase, ATPase at pH 9*4, 4 6, and4*3, and acid phosphatase. Specimens for elec-tron microscopy were fixed in glutaraldehyde,stained with uranyl acetate and lead citrate,and were examined in a Philips EM410 elec-tron microscope. Ragged red fibres were quan-tified in biopsies from the deep muscle groupon a MOP dedicated digitiser for quantitativemicroscopy (Kontran, Messgerate, GMBH),counting at least 200 fibres.The prevalence of histological abnormalities

with age was compared in the two groups. Ascore was simply derived for each biopsy byawarding a point for each of four main histo-logical abnormalities-namely, the presence ofragged red fibres, selective type 2 atrophy,core-targetoid fibres, and necrotic fibres, andsummating the result for the superficial anddeep biopsy (therefore allowing a maximumscore of eight). The score does not attempt toweight the histological abnormalities and issimply designed to facilitate comparisonbetween groups.

Electron microscopy confirmed that raggedred fibres represented fibres in which therewere subsarcolemmal and intermyofibrillaraccumulations of mitochondria. Most of theaccumulated mitochondria did not appearmorphologically abnormal, but inclusionswere seen in a few. The most usual type con-

sisted of single, rounded, amorphous inclu-sions, sometimes seen in longitudinal section.More rarely, an inclusion with internal struc-ture was found (fig 3A). In patients in whom

core-targetoid structures were found, electronmicroscopy showed fibres with central disrup-tion and streaming of the myofibrillar architec-ture (Fig 3B).As noted, the prevalence and severity of

these abnormalities were similar in the studyand control groups, and in the study groupthere was little apparent difference betweenthe patients with rheumatoid arthritis and cer-

vical spondylosis. The prevalence of pathologi-cal abnormalities increased with age in both

groups, being much less in patients under 60

years of age. This was illustrated by an

increase in the mean total score of histologicalabnormalities with age. The increase in patho-logical findings with age was also reflected inan increased prevalence of patients withragged red fibres (study group < 59 years 0%,> 60 years 75%; control group < 59 years

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Figure 2 (A) Gomori trichrome preparation showing a"ragged red" muscle fibre, with accumulation of material(red in colour with this preparation) in a subsarcolemmaland intermyofibrillar location. (B) Histochemicalpreparation for cytochrome oxidase showing a fibre withthe morphology ofa "ragged red"fibre, and an adjacentfibre both showing an absent staining reaction. Otherfibresin the field show a patchy staining reaction. (C) NADH-TR preparation showing core-targetoidfibres with a welldemarcated central absence ofstaining reaction;magnification x 280.

29%, > 60 years 88%). The mean percentageof ragged red fibres per muscle also increasedwith age in both the study and control groups,

A and indeed was greater in the control group atall ages. The range of values for percentage ofragged red fibres per muscle also increasedwith age, becoming very wide in the older pop-ulation, and ranging from several patients withno ragged red fibres to patients with consider-able numbers (study group < 59 years, meanpercentage ofragged red fibres per muscle 0%,range 0%, interquartile range (IQR) 0%; studygroup > 60 years, mean 1 89%, range 0%-12-38%, IQR 0-1-19%; control group < 59years, mean 0d17%, range 0%-0 77%, IQR0%-0-19%; control group > 60 years, mean4-89%, range 0%-34-12%, IQR 1-07%-4-69%).

Discussioni; .We have shown profound pathological abnor-Abmalities in both superficial and deep cervical

paravertebral muscle groups. The presence oftype 1 predominance is perhaps not surprisingin a group of muscles with a largely posturalfunction. The presence of denervation in sev-eral patients, indicated by angular atrophicfibres and grouped atrophy, can probably beaccounted for by nerve root compression due

pj to bony abnormalities of the cervical spine.t Core-targetoid fibres, present in a higher pro-

portion of patients, may also reflect denerva-tion. In addition to these findings, however,there is a high prevalence of myopathic fea-tures, including type 2 fibre atrophy, raggedred fibres, and scattered necrotic fibres.The prevalence and severity of these abnor-

malities was similar in both the study groupand the control necropsy population. Indeed,

*@ although a slightly higher proportion of thesg study group showed denervation changes, the

prevalence of other abnormalities such asragged red fibres, was higher in the controlgroup. A necropsy group is, clearly, not theperfect control (an age and sex matched, oth-

"' erwise well population, biopsied in life withimaging established healthy cervical spines),and some may have had a degree of cervicalspondylosis which is common with increasing

F age. Nevertheless, our control population hadno clinical history of cervical spine disease andnone had been subjected to operation for suchdisease, so that any spinal disease present wascertainly much less severe than in the studygroup. This being the case, our data reject thehypothesis that the pathological changes in themuscles are secondary to the cervical spinedisease, there being no difference between the

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Figure 3 (A) Electron micrograph shows a mitochondrial inclusion with internal

structure. The single inclusion runs the length of the mitochondrion and shows parallelelectron dense lines; magnification x 50 000. (B) Electron micrograph of a muscle fibre

showing central myofibrillar streaming; magnification x 5800.

two groups. Rather, in both groups, the patho-

logical abnormalities become more severe and

more prevalent with increasing age, so that

this seems to be an age related muscle disor-

der.

Selective type 2 fibre atrophy was a com-

mon finding and is a well recognised, non-spe-

cific finding with many causes,9 which, in our

patients, might include various combinations

of disuse atrophy, intercurrent illness, and

drugs (for example, corticosteroids).

The age related presence of ragged red

fibres is a more intriguing finding. These are,

of course, associated with primary mitochon-

drial diseases."'01' However, ragged red fibres

occur in other diseases, not primarily consid-

ered to be disorders of mitochondrial DNAsuch as inclusion body myopathy, in whichthey are associated with mitochondrial DNAdeletions.12 In this disease the ragged red fibreshave been suggested to arise by clonal expan-sion of mitochondrial DNA with a deletion inregenerating muscle after segmental necrosis.13IThis is a mechanism which may be relevant toour patients, in which there is evidence ofmuscle fibre damage. Ragged red fibres havealso been found in lumbar spinal muscles ofpatients with progressive lumbar kyphosis andin patients operated on for lumbar spinal discdisease.'14 We have also found them in lumbarspinal muscles (unpublished observations)suggesting that they may be a particular fea-ture of aging in postural muscles. Cytochromeoxidase deficient fibres increase with aging inmuscle,'" and deletions of mitochondrial DNAincrease with aging,'16 18 possibly secondary toprolonged free radical damage. It remains tobe determined whether the age relatedincrease in ragged red fibres in the paraspinalmuscles in our study is arising secondary toacquired alteration in mitochondrial DNA, orto some other mechanism.

It is also of note that ragged red fibres andcore-targetoid fibres, as found in our patients,have both been produced in an experimentalmodel of acute muscle ischaemia.'9 In particu-lar, in this ischaemic model the ragged redfibres ultrastructurally showed mitochondriacontaining similar, amorphous, single,rounded electron dense inclusions as seen inour patients, a type of inclusion not, to ourknowledge, described in mitochondrialcytopathies.

In conclusion, the paraspinal muscles inboth our study group and control groupshowed increasing pathological abnormalitieswith age. Both myopathic features and fea-tures of denervation were seen, so that this agerelated muscle disorder may have both a myo-genic and neurogenic component. Whateverthe precise pathogenesis, it seems probablethat such striking pathological findings areassociated with functional impairment of thisgroup of muscles with increasing age, and thusmay contribute to the pathogenesis and symp-tomatology of cervical spine disorders and toinstability of the cervical spine in those withsevere bony disease. The state of these mus-cles is therefore of clinical relevance and meth-ods to improve their strength may be of value inthese patients. Non-invasive methods, such asMRI, do provide information as to the state ofmusculature,20 and may be of value in theassessment and follow up of some of thesepatients.We thank Mr G Gatward for excellent technical work in thepreparation of material for electron microscopy and Mr CBurton for help with photomicrography.

1 Long DM. Lumbar and cervical spondylosis and spondy-lotic myelopathy. Curr Opin Neurol Neurosurg 1 993;6:576-80.

2 Pemeczky G, Bock FW, Neuhold A, Stiskal M. Diagnosisof cervical disc disease. MRI versus cervical myelogra-phy. Acta Neurochir 1992;116:44-8.

3 Toumade A, Patay Z, Tajahmady T, Braun JP, Million 8,Schmutz G. Contribution of discography to the diagnosisand treatment of lumbar disc hemiation. _7 Neuroradiol

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Paravertebral muscles in disease of the cervical spine

4 Gomez MR. The clinical examination. In: Engel AG,Franzini Armstrong C, eds. Myology. 2nd ed. McGrawHill, 1994:746-63.

5 Brooke MH, Fenichel GM, Griggs RC, et al. Duchennemuscular dystrophy: patterns of clinical progression andeffects of supportive therapy. Neurology 1989;39:475-81.

6 Dubowitz V, Heckmatt J. Management of muscular dystro-phy. Pharmacological and physical aspects. Br Med Bull1980;36:139-44.

7 Frost H, Klaber Moffett JA, Moser JS, Fairbank JCT.Randomised controlled trial for evaluation of fitness pro-gramme for patients with chronic low back pain. BMJ1995;310: 151-4.

8 Malmivaara A, Hakkinen U, Aro T, et al. The treatment ofacute low back pain-bed rest, exercises, or ordinaryactivity? N EnglJ Med 1995;332:351-5.

9 Banker BQ, Engel AG. Basic reactions of muscle. In: EngelAG, Franzini Armstrong C, eds. Myology. 2nd ed.McGraw Hill, 1994:832-88.

10 Yamamoto M, Clemens PR, Engel AG. MitochondrialDNA deletions in mitochondrial cytopathies: observa-tions in 19 patients. Neurology 1991;41:1822-8.

11 Schapira AHV. Mitochondrial cytopathies. Curr OpinNeurobiol 1993;3:760-7.

12 Oldfors A, Larsson NG, Lindberg C, Holme E.Mitochondrial DNA deletions in inclusion body myositis.Brain 1993;116:325-36.

13 Oldfors A, Moslemi AR, Fyhr IM, Holme E, Larsson NG,

Lindberg C. Mitochondrial DNA deletions in musclefibres in inclusion body myositis. J Neuropathol ExpNeurol 1995;54:581-7.

14 Delisle MB, Laroche M, Dupont H, Rochaix P, RumeauJL. Morphological analysis of paraspinal muscle: compar-ison of progressive lumbar kyphosis (camptocormia) andnarrowing of lumbar canal by disc protrusions.Neuromuscul Disord 1993;3:579-82.

15 Muller-Hocker J. Cytochrome c oxidase deficient fibres inthe limb muscle and diaphragm ofman without musculardisease: an age-related alteration. Jf Neurol Sci 1990;100:14-21.

16 Corral-Debrinski M, Horton T, Lott MT, Schaffner JM,Flint Beal M, Wallace DC. Mitochondrial DNA dele-tions in human brain: regional variability and increasewith advanced age. Nat Genet 1992;2:324-9.

17 Cortopassi GA, Arnheim N. Detection of specific mito-chondrial DNA deletion in tissues of older humans. NuclAcids Res 1990;18:6927-33.

18 Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mito-chondrial DNA mutations as an important contributor toageing and degenerative disease. Lancet 1989;i:642-5.

19 Heffner RR, Barron SA. The early effects of ischaemiaupon skeletal muscle mitochondria. J Neurol Sci 1978;38:295-315.

20 Claque JE, Roberts N, Gibson H, Edwards RHT. Muscleimaging in health and disease. Neuromuscul Disord 1995;5:171-8.

NEUROLOGICAL STAMP

Thomas Sydenham (1624-89)

The 17th century physician, Thomas Sydenham, becameknown as the English Hippocrates. He studied medicineat Oxford where the dentist Robert Boyle and the physi-cian and philosopher John Lock were his friends. JohnLock gave a detailed account of trigeminal neuralgia in aseries of letters in 1667 and Sydenham made contribu-tions to the same condition. Sydenham's education wasinterrupted by the English Civil War. His father and fourbrothers were serving in Cromwell's army. Thomas alsoenlisted and served for four years as Captain of a Troop ofHorse after which he returned to Oxford, gaining his MBin 1648. His medical studies continued at Montpellierwhere Rabelais (1490-1553) had earlier been Professor ofMedicine.

Sydenham understood the need for careful bedsideobservation of clinical phenomena. His attitude towardshis contemporaries was indifferent or scornful and hecomplained bitterly of the opposition and rejection of hisown colleagues. His painstaking observations and excel-lent description of many diseases were recorded in hisObservationes Medicae (Medical Observations) (1676). Hisfame largely rests on his first hand account of diseasesincluding hysteria and his description of chorea minor.He was a sufferer from gout and his treatise on this subjectTractatus de podagra (1683) is considered a masterpiece.The Dissertatio Epistolaris (1682) contains his classicaccount of hysteria. Sydenham's description of choreaminor, which he saw as a kind of convulsion, is found in hisSchedula Monitoria (1686).Sydenham was one of the first to prescribe iron for

anaemia and he popularised the use of quinine yieldingcinchona bark introduced from Peru in the treatment ofague or malaria. Syphilis he treated by mercurial inunc-tions until free salivation occurred and he believed that itwas the salivation, rather than the mercury, that wrought

the cure. Opium was a favourite drug in the form of atincture to which he added saffron, cloves, and cinnamon."Sydenham's laudanum" as it was called remained a pop-ular remedy for many years. His service to medicine wasnot to speculate but to lead people back to the bedside.His great success as a physician led Boerhave, when lec-turing in Leyden, always to raise his hat on mentioningthe name of Sydenham. He had a dignified ethical regardfor his patients, holding himself "answerable to God" fortheir care. This may not have fitted easily into a modernmanagement environment, but his comment "I have con-sulted my patients' safety and my own reputation mosteffectually by doing nothing at all" would, no doubt, havebeen looked upon more favourably.

After he left All Souls College he moved to Londonwhere he spent the rest of his life in private practice.Although he has not been honoured postally, he was hon-oured in this United States postmark of 1934, 310 yearsafter his death. The postmark contains a spelling error.He died at his house in Pall Mall and was buried in StJames's Church, Piccadilly, where the College ofPhysicians, in 1810, erected a tablet to his memorK.

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