74ournal of Neurology, Neurosurgery, and Psychiatry 1995;58:742-744

SHORT REPORT

Motor neuron disease (amyotrophic lateralsclerosis) arising from longstanding primarylateral sclerosis

R P M Bruyn, J H T M Koelman, D Troost,JM B V de Jong

AbstractThree men were initially diagnosed as

having primary lateral sclerosis (PLS),but eventually developed amyotrophiclateral sclerosis (ALS) after 7-5, 9, and atleast 27 years. Non-familial ALS andPLS might be different manifestations ofa single disease or constitute completelydistinct entities. The clinical diagnosis ofPLS predicts a median survival that isfour to five times longer than in ALS.

(J Neurol Neurosurg Psychiatry 1995;58:742-744)

Keywords: amyotrophic lateral sclerosis; primarylateral sclerosis

Department ofNeurology, OudenrynHospital, Utrecht, TheNetherlandsR P M BruynDepartment ofNeurologyJ G T M KoelmanJM B V de JongDepartment ofPathology, GraduateSchool ofNeurosciencesAmsterdam,Academic MedicalCentre, Amsterdam,The NetherlandsD TroostCorrespondence to:Dr RPM Bruyn,Department of Neurology,Oudenryn Hospital, 1 vanHeuven Goedhartlaan, 3527CE Utrecht, TheNetherlands.Received 1 November 1994and in revised form16 February 1995.Accepted 24 February 1995

Primary lateral sclerosis (PLS), defined as

non-familial progressive spinobulbar or bul-bospinal spasticity-without amyotrophy, fas-ciculation, optic atrophy, deafness, or pedescavi and with no more pronounced sphinc-ter disturbances than urgency of micturition,and not caused by a segmental lesion, is rare.

Its status as a nosological entity, separatefrom the hereditary spastic paraplegias on theone hand and amyotrophic lateral sclerosis(ALS) on the other, remains disputed.Mulder' suggested that ALS begins withperipheral weakness, and Pringle and cowork-ers diagnose PLS on initial central motor

deficit.2Gowers described the first patients with

progressive spastic paraparesis, eventuallycomplicated by amyotrophy.3 Spiller reportedeight patients of whom bulbar or limb spas-

ticity was the initial sign.4 This was followedby lower motor signs in six, but remained as

the only sign in two. Wilson' and Brouwer6claimed to have seen similar patients with a

long standing spastic paraparesis eventuallyfollowed by wasting in the hands.

Our three patients (one with a necropsy)demonstrate that longstanding PLS may

change into ALS.

Case reportsCASE 1In 1984, at the age of 45, a previously healthymanager experienced trouble in maintaininghis balance, and noticed slowly progressivestiffness of the left leg with cramps. The

family history was negative and consanguinitywas excluded. Examination disclosed slightweakness of the left thigh muscles, mild spas-ticity of the legs, knee and ankle cloni, andextensor plantars. Blood chemistry, CSF, andEMG were unremarkable. Magnetic reso-nance imaging of the cervical spine was nor-mal and PLS was diagnosed. Micturitionurgency began in 1987. Examination in 1988showed definite spastic paraparesis and mildproximal weakness of the legs. Sural and tib-ial nerve somatosensory evoked potentials(SSEPs) were bilaterally absent and delayedrespectively. Visual and brainstem auditoryevoked potentials (VEPs, BAEPs), and brainMRI were normal. By 1990, walking hadbecome troublesome and dysarthria was pre-sent; the calves showed fasciculation andsome atrophy. The left extensor hallucis mus-cle was paralytic and the right comeo-mandibular reflex was now positive. During1991 and 1992 dysarthria, forced laughter,and generalised weakness progressed andamyotrophy became evident. Examinationnow disclosed widespread fasciculation oftrunk and limb muscles, considerable amy-otrophy, most pronounced in the lower legs,and brisk masseter and bilaterally positivecomeomandibular reflexes. The diagnosiswas changed to that of ALS. Repeat EMG in1993 showed very low compound muscleaction potentials (CMAPs) of the intrinsicfoot muscles bilaterally. Denervation activityseemed limited to the anterior tibial muscles,whereas re-innervation activity was seen inthe limb musculature. The patient continuesto deteriorate slowly.

CASE 2In 1983, at the age of 39, a previously healthyplumber noticed slurring of speech. Thefamily history was negative; no consanguinitywas present. Examination of this otherwisehealthy right handed man of athletic builddisclosed minimal dysarthria, increased ten-don jerks, and positive comeomandibularreflexes. Physical examination and extensivestudy of blood chemistry and CSF were unre-markable. An EEG and brain CT were nor-mal. No definite diagnosis was made. In1984, the patient developed a mild rightsided hemiparesis and ankle cloni. Spasticparaparesis and extensor plantars became evi-dent in 1985. Sural and tibial nerve SSEPs

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Motor neuron disease (amyotrophic lateral sclerosis) arisingfrom longstanding primary lateral sclerosis

were bilaterally absent; median nerve SSEPsand EMG were normal and PLS was diag-nosed. In 1989, atrophy of the interosseoushand muscles became apparent, with fascicu-lation of wrist and finger extensors. Sensationremained intact. Electromyography showedsigns of re-innervation but no evidence ofdenervation. Conduction velocities were nor-mal. Magnetic resonance imaging showedsome thinning of the cervical cord but nobrain abnormalities. Amyotrophy spread toinvolve the forearms and eventually the lowerlegs. Repeat EMG in 1991 disclosed fibrilla-tion and positive sharp waves in the left ante-rior tibial muscle; in 1993 very low CMAPsof the extensor digitorum communis muscleswere noted, as well as denervation activity inboth tibial anterior muscles, the rectusfemoris, and the first interosseous muscle,with fasciculations. Re-innervation activity

Figure 1 Spinal cord at level C7. Widespread immunoreactivity for MHC common

framework antigen is present in lateral and anterior columns. There is mild staining in theanterior horns (bar represents 1 5 mm).

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"'Xw. 4

& E, r

1,*'~ ~ X

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Figure 2 Numerous cells in the white matter of the spinal cord expressing MHC common

framework antigen (bar represents 70 pm).

was seen in the distal and proximal limbmuscles.The diagnosis was changed from PLS to

ALS. The course remains slowly progressive.

CASE 3In 1957, a 33 year old office clerk was admit-ted for analysis of a heavy feeling in his legsand cramps in the calves and proximal legmuscles, progressive complaints that hadbegun at the age of 27. There was no consan-guinity and the family history was negative.On admission, hyperreflexia of arms and legswas found with a patellar clonus, and a leftextensor plantar sign; CSF was normal andPLS was diagnosed. His condition deterio-rated very slowly. Examination in 1978showed moderate spasticity of both legs, kneeand ankle clonus, Babinski signs, and aslightly decreased vibration sense at theankles. Fasciculations or atrophy were notpresent. Cervical myelography was normal.Electromyography showed decreased conduc-tion velocities of both peroneal nerves with nodenervation activity. The patient was lost tofollow up but was necropsied in 1989, havingdied of pneumonia.

There were no gross alterations to thebrain. The spinal cord and the anterior rootsshowed mild atrophy. Microscopy showed asevere loss of spinal anterior horn cells, asubtotal at the dorsolumbar and mild atthe cervicodorsal level. Mild cell loss wasnoted in Clarke's columns. Numerousamylaceous bodies and occasional instancesof neuronophagia with considerable reactivegliosis were evident throughout the cord.A pronounced myelin pallor characterisedthe pyramidal tracts. Macrophages and acti-vated microglial cells immunocytochemicallystained with Tal 1 B5 (MHC common frame-work antigen) antibody (Bodmer; dilution1:20) on paraffin slides (for method see vanden Bergh et a17) were strongly positive in theentire spinal cord (figs 1 and 2), except theposterior funiculi. Lymphocytic infiltrationwas not present. The diagnosis was changedto ALS.

DiscussionThe El Escorial diagnostic criteria8 for ALSinclude both upper (spasticity, hyperreflexia,extensor plantar signs, increased gag andsnout reflexes, and pseudobulbar effect) andlower (asymmetric weakness, atrophy, fascic-ulation) motor neuron signs. The onset isinsidious, its course invariably progressive,usually without sensory involvement(although sensory pathways may beaffected9 10), and survival is inversely relatedto age at diagnosis." 12 Clinical diagnostic cri-teria for PLS include an insidious adult onsetof spastic paresis, usually beginning in thelegs, without a family history, running aslowly progressive course of at least threeyears, ultimately leading to a severe spasticspinobulbar paresis, and atrophy of the pre-central gyrus on MRI.'The debate-whether PLS is a distinct

nosological entity or a forme fruste of ALS-

743

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Bruyn, Koelman, Troost, de J7ong

is still going on. According to Mackay,'3 PLSis simply ALS without lower motor neuronsigns, which are bound to appear unless deathsupervenes. In his series of 70 deceasedpatients with ALS 11 presented with purelyspastic features for several years before mus-cle atrophy became manifest. Only onepatient remained purely spastic until death.He excluded three patients, alive at the timeof study, who had had purely spastic paresisfor as long as 21 years. The study did notmention EMG. In a thorough clinicopatho-logical study,'4 four patients clinically hadPLS. In three of these patients, the time fromonset of symptoms until death was short(16-30 months). A fourth patient (case 43),with a spastic spinobulbar paresis, died eightyears after onset. Necropsy showed loss ofmotor cells and of anterior root fibres, butalso a multiple myeloma with lesions in sev-eral vertebrae, although compression or infil-tration of the cord had been excluded.

Younger et al'5 reported three necropsiedcases of PLS, with a disease duration of 1,5-5, and 10 years. These patients showed iso-lated symmetric demyelination of the corti-cospinal tracts at all spinal levels, withoutinvolvement of anterior or dorsal columns,without gliosis or Betz cell loss in the precen-tral gyrus, and without decrease of motorneurons in brainstem nuclei or the spinalcord. Fisher'6 reported one necropsied case ofchronic bilateral spinobulbar spasticity with afive year survival, finding demyelination ofmedullary pyramids and lateral corticospinaltracts at all spinal levels, and probably areduced number of Betz cells in the motorcortex. A second case of pure spastic para-paresis, with a disease duration of less thantwo years, showed selective demyelination ofthe lateral corticospinal tracts without abnor-malities of the brain and brainstem. Beal andRichardson'7 described a necropsy of awoman with a 3-5 year history of PLS. Thisshowed a severe loss of Betz cells in the pre-central gyrus, atrophic medullary pyramids, aparamedian pontine infarct, and demyelina-tion of anterior and lateral corticospinal tractsat all spinal levels.

Correct diagnosis in patients with achronic progressive spastic paraparesis,"'

tetraparesis, and spinobulbar paresis'9 willremain a diagnostic challenge.To avoid unnecessary distress to patients,

retention of the diagnosis of PLS may be jus-tified, because of its favourable prognosiscompared with ALS with lower motor neurononset.

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