Strümpell's familial spastic paraplegia: an electrophysiological demonstration of selective central distal axonopathy

Electroencephalograpl~v and clinical Neuroplo,siologv, 1987, 6 6 : 1 3 2 - 1 3 6

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Elsevier Scientific Publishers Ireland, Ltd.

E E G 03256

Short communication

Str mpell's familial spastic paraplegia: an electrophysiologicai demonstration of selective central distal axonopathy Antonino Uncini, Maurizio Treviso, Mario Basciani and Domenico Gambi Institute of Neurological Sciences, LaboratoO, of Clinical Neurophvsiologv, Uni~ersitv of Chieti, ('hieti (ltalv) (Accepted for publication: 11 September, 1986)

Summa~ Three patients with autosomal dominant Strfimpell's familial spastic paraplegia (SFSP) were evaluated by means of somatosensory evoked potentials (SEPs) from upper and lower limb and determination of sural nerve conduction velocity. Findings of normal sural nerve conduction but reduced amplitude and poor definition of SEPs with normal latencies on peroneal nerve stimulation support a pattern of central nervous system degeneration characterized by a selective involvement of centrally directed axons within the gracile fasciculi. Key words: familial spastic paraplegia: dying back: axonopathy: SEP

St~mpell's familial spastic paraplegia (SFSP) is a rare hereditary disorder characterized by progressive weakness and spasticity affecting predominantly the lower limbs. In adult cases there is also impairment of deep sensory modalities. The pathological alterations are: corticospinal tract degeneration caudal to the medullary pyramids and posterior column degeneration increasing rostrally without loss of dorsal root fibers and intact peripheral nerves (Greenfield 1954; Schwartz and kiu 1956; Behan and Maia 1974). Recent electrophysiological data (McLeod et al. 1977: Thomas et al. 1981; Dimitrijevic et al. 1982) suggest that SFSP may be characterized by a pattern of nervous system degeneration called 'central-distal axonopathy' (Thomas 1982).

Patients and methods The observations were made on 3 patients: the father and two dizygotic twins ages 57 and 29 years respectively. All had lower limb spasticity and weakness that began at 20 years in the father and 8 and 10 years respectively in the daughter and the son and progressively increased. All patients had increased tone and brisk tendon reflexes in lower limbs and extensor plantar responses and had ankle clonus and bilateral pes cavus. Two of them, the father and the daughter, also had hyperreflexia in the upper limbs. Moreover, the father had reduced

Correspondence to: Antonino Uncini, M.D., Present address: The Neurological Institute of New York, Box No. 60, 710 West 168th Street, New York, NY 10032, U.S.A.

appreciation of vibration and position sense in the lower extremities without impairment of other sensory modalities. Gait was spastic and canes were required. In order to explore the function of the peripherally and centrally directed axons of the primary sensory neurons, somatosensory evoked potentials (SEPs) were obtained by upper and lower limb stimulation and sural nerve conduction velocities were determined. To obtain SEPs from lower limbs the peroneal nerve was stimulated at the popliteal fossa b y subcutaneous needle electrodes. Square pulses (0.1 msec duration and 8 Hz) were delivered with an intensity sufficient to produce a visible foot dorsiflexion. The cauda equina responses were recorded using surface electrodes placed at the 3rd and 1st lumbar spinous processes (L3-L1). The scalp exploring electrode was placed at Cz' (2 cm behind Cz) with reference at Fpz' (midpoint between Fpz and Fz, 10-20 international system). The amplified and filtered signals (gain l03, filtering band with 20-2000 Hz at - 3 dB/oct) from lumbar and scalp electrodes were averaged over 70 msec post stimulus. Two to 3 averages, each of 2000 artifact-free responses were superimposed through an x-y plotter. According to Rossini et al. (1981), to display better short latency SEPs, the responses were filtered through a digitally restricted bandpass (200-2000 Hz) that removed the lower frequency components and permitted display of the early latency peaks that are thought to arise in subcortical and cortical structures (Fig. 1). The knee-cauda conduction time was measured at the onset of the initial lumbar negative deflection, while the corresponding conduction velocity was obtained by dividing the knee-lumbar distance expressed in m m by the cauda response latency. The L3-scalp conduction time, considered to represent a reliable

0013-4649/87/$03.50 ,~'~1987 Elsevier Scientific Publishers Ireland, Ltd.

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lated at the wrist (0.1 msec duration and 5 Hz) with an intensity producing a moderate thumb twitch. Recordings were made at Erb's point, over the spinous process of the 7th cervical vertebra and in the hand sensory area (2 cm behind C3 and C4, 10-20 international system). The reference was placed on the earlobe contralateral to the stimulated side. Erb's point, cervical and scalp responses were averaged using a 30 msec analysis time. Two to 3 averages each of 1000 artifact-free responses were superimposed and plotted. Cervical N13, scalp N20 and scalp P14-N20 intervals were taken into consideration in order to calculate the central conduction time (CCT). Sensory nerve action potentials were recorded over the sural nerve antidromically with an active electrode posterior and below the lateral malleous of the fibula stimulating on the posterior aspect of the leg 15 cm above. The temperature of the stimulated limb was maintained between 34 and 3 6 ° C by a thermistor-infrared heating system.

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Fig. 1. Lumbar response (above) and scalp SEPs (below) from right peroneal nerve stimulation in a healthy volunteer recorded with an open bandpass filter (20-200 Hz, upper tracings of each couple) and after digital filtering (200-2000 Hz, lower tracings). Note that after digital filtering the short latency wavelets from the scalp become more evident. Peaks are labeled conforming to the Guidelines of the Italian and American EEG Societies.

In all the patients, the wrist-Erb's point conduction velocities, the latencies of the cervical and scalp responses from median nerve stimulation as well as the interpeak N13-N20 and P14-N20 latencies were normal (Table I). Sural conduction velocity was 5 6 . 0 + / 3.1 m / s e c and SNAP amplitude was 23.5 + / 3.4 #,V (control values of 20 normals: 54.4 + / 5.2 msec and 18.5 + / 6.3 t~V). Cauda equina responses were always recordable and the knee-cauda conduction velocity was: 70.1 + / 2.4 m / s e c (control values: 68 + / 4.3 m/sec). In patient 3 with open filters only a well defined initially positive diphasic complex with a latency of 48.7 msec was recognizable in scalp SEPs from peroneal nerve stimulation (Fig. 2). If L3-scalp conduction time (CCT) is calculated to the positive peak, it appears greatly slowed: 41.7 msec compared to 16.7 + / 1.27 msec for normals (Rossini and Trcviso 1983). However, if the response is filtered through a digitally restricted bandpass (200-2000 Hz), a low amplitude (0.05 #V) poorly defined complex indicated by a dot in Fig. 2, with a positive peak at 24.8 msec, appeared. CCT calculated by means of this positive peak is normal. In the remaining 2 patients with open filters, a P27 peak with normal latency (M: 27 msec) and reduced amplitude (M: 0.52 ~V) was recogniz-

evaluation of central conduction time (CCT), was measured by subtracting the lumbar response latency from that of the scalp P25 peak in controls and in patients (Rossini and Treviso 1983). This wave was selected as latency indicator because it is more stable than longer latency potentials and is thought to reflect the first identifiable components of the scalp recorded response which arises in somatosensory cortex (Rossini et al. 1981, 1985). The straight line distance between L3 and vertex Cz' recording electrode divided by the difference of lumbar and vertex latency provides an approximate estimation of conduction velocity from the spine to somatosensory cortex (Rossini and Treviso 1983). To obtain somatosensory evoked responses from the upper limbs, the median nerve was stimu-

TABLE I Wrist-Erb's point conduction velocity; cervical N13; scalp P14, N20 peak and interpeak (N13-N20, P14-N20) latencies to unilateral median nerve stimulation in controls and in patients with SFSP.

Controls Patients

M S.D. M S.D.

Wrist-Erb's point (m/sec)

Cervical N13 latency (msec)

Scalp P14 (msec)

Scalp N20 (msec)

CCT N13-N20 (msec)

CCT P14-N20 (msec)

68.94 4.13 70.4 1.69

13.03 0.46 12.7 0.8

13.76 0.96 14.1 1.0

18.26 0.94 18.1 1.28

5.86 0.45 5.36 1.02

4.32 0.41 4.6 0.29

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able (Fig. 3). In controls, peak P27 had a latency of 27.5 + / 2.1 msec and amplitude measured against the following negative component, of 2.1 + / 0+8 /~V (Rossini et al. 1985). Restricted filtering failed, however, to show all the shorter latency, high frequency wavelets, observed in normals (Fig. 1) and only the P25, P27, N29 components were better defined (Fig. 3). Further, in both patients, with open bandpass, a more evident positive-negative complex with a mean latency of 48.4 msec, indicated by a triangle in Fig. 3 was also recorded.

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Fig. 2. Cauda and scalp responses from right peroneal nerve stimulation of patient no. 3. Cauda response (upper tracing) is present and peripheral knee-cauda conduction velocity is normal as well as in the 2 other patients. Scalp SEPs recorded with open bandpass filtering (intermediate tracings) seem to evidentiate only a delayed (48.7 msec) positive-negative complex indicated by a triangle. If central conduction time (CCT = L3Cz') is measured from the onset of cauda response and the onset of the delayed positive response (dashed line) it results greatly increased (41.7 msec) respect to our normal values (16.7 + fl 1.27 msec). Digital filtering (lower tracings) revealed a little amplitude but quite discernible positive peak with a latency of 24.8 msec. CCT calculated basing on this response is normal.

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Fig. 3. Scalp SEPs from right peroneal nerve stimulation of the patients 1 and 2. In the upper tracings of each couple recorded by open bandpass filtering (20-2000 Hz) a little amplitude complex, indicated by a point, is detectable. Digital filtering (200-2000 Hz) better defines P25-P27 peaks but the short latency wavelets present in controls are lacking. The evident positive-negative complex, indicated by a triangle, at the edge of the 70 msec analysis window can be interpreted as a normal latency P2 component according to Tsumoto's nomenclature.

SFSP represents a model of degeneration of axons that progresses back towards the cell body. Greenfield (1954) introduced the term 'dying back' of axons towards the cell body. Subsequently, Spencer and Schaumburg (1976, 1977) called these disorders 'central peripheral distal axonopathy' pointing out that the longest and largest fibers in the central and peripheral nervous system showed a distal axonal degeneration. In SFSP the corticospinal and posterior column tracts, that contain the longest fibers in the central nervous system, are involved but there is no evidence for degeneration of peripheral nerves or nerve roots (Behan and Maia 1974) confirming a selective distal axonopathy affecting only the central processes of the primary sensory neurons. In our patients, normal peripheral nerve conduction studies, including Erb's point and cauda responses, are consistent with the above mentioned neuropathological reports. Similar electrophysiological data were previously reported (McLeod et al. 1977; Thomas et al. 1981). The latencies of cervical N13 somatosensory evoked potential, scalp P14 and central conduction times (N13-N20 and P14-N20) from median nerve stimulation were normal. The exact neural origin of the cervical components still remains to be elucidated but N13 is thought to probably originate in the cervical spinal cord or cuneate nucleus (Yamada et al. 1980), with scalp P14 originating in the medial lemniscus (Desmedt and Cheron 1980). Thomas et al. (1981) reported in 6 out of 18 cases of SFSP an absence of spinal N13 potentials and in the remainder a reduction of the amplitude of N13 wave, which when present had normal latency. Our results would seem to confirm the neuropathological reports of minor involvement of the fibers coming from the upper limb running in the cuneate fasciculi. Electrophysiological studies of posterior column function are scanty. Dimitrijevic et al. (1982) reported delayed cortical responses from peroneal nerve stimulation in 3 affected subjects, in 2 relatives with only exaggerated reflexes and also in 4 unaffected relatives. Abnormalities consisted of delayed P1 or P2 peaks according to Tsumoto's nomenclature (Tsumoto et al. 1972), or in poor definition of the components. These findings were ascribed to impaired conduction in the ascending pathways giving rise to temporal dispersion. Pederscn and Trojaborg (1981) reported a normal N14 cervical potential recorded from C3 in 13 patients with SFSP but a delayed N20 and a slowed N14-N20 interval from median nerve stimulation in 2 cases. In 3 cases, the latency of P40 SEP component from tibial nerve stimulation was delayed.

STRUMPELL'S FAMILIAL SPASTIC PARAPLEGIA In one of our patients by open filter recording (20-2000 Hz) only a well recognizable positive-negative complex, apparently delayed, was recorded (Fig. 2). L3-scalp conduction time was slowed and if conduction velocity from cauda to vertex was calculated it was greatly reduced (15.6 m/see) compared with normal values (38.72 + / 2.3 m/sec) (Rossini and Treviso 1983) and also with the values obtained in patients affected by multiple sclerosis (Rossini et al. 1985). Restricted bandpass disclosed in this patient and made more obvious in the others only the P25, P27 peaks of the short latency SEP components (Figs. 2 and 3). Central conduction time and conduction velocity calculated from these responses were normal. In other reports slowed conduction of SEPs found in patients with SFSP was related to central demyelination or loss of large myelinated fibers (Pedersen and Trojaborg 1981: Dimitrijevic et al. 1982). From the neuropathological point of view, it is generally accepted that axonal degeneration is the main feature of SFSP (Behan and Maia 1974). Our findings of short latency SEPs with reduced amplitude or even absent responses from peroncal nerve stimulation recording with open filters and poorly defined components using restricted bandpass filtering suggest axonal degeneration of posterior column rather than demyclination. In a distal axonopathy the few surviving large diameter ascending fibers are still capable of generating a response of normal latency, although reduced in amplitude. As reported by Rossini et al. (1985), peroneal scalp SEPs in multiple sclerosis are frequently absent or delayed suggesting a block of nervous impulse propagation or asynchronous conduction in demyelinated axons. In only one SEP of the 68 reported cases it was possible to record a normal P27 with oi)en filters which was different from healthy controls lacking short latency ~avelets using restrict filtering. Regarding the large amplitude positive-negative complex recorded in our patients with open filters and indicated by a triangle in Figs. 2 and 3, it can be interpreted as a normal latency P2 component according to Tsumoto's nomenclature (Tsumoto et al. 1972). The phenomenon of absent or ill-defined short latency SEPs followed by normal subsequent late wa~es could be explained by the amplifying characteristics of the cortical relays. This property permits to record postsynaptic responses, even in presence of low amplitude or highly desynchronized afferent inputs which are not or hardly sufficient to elicit short latency wavelets at the scalp recording electrodes (Yamada et at. 1981; Satya-Murti et al. 1983). In conclusion, our study confirms that in SFSP there is a selective degeneration of the centrally directed axons of the dorsal root ganglion cells, especially of the longest fibers from the lower limbs running in the gracite fasciculi, responsible for reduced amplitude, poorly defined but with normal latency early scalp response~ R~sum~

Paraplegic ~astique farniliale de Striirnpell: une d&nonstration ~lectrophvsiologique d'axonopathie centrale distale s$lective Trois patients avec parapl6gie spastique familiale autosomique dominante de Strtimpell (SFSP) ont ~t~ ~tudi~s 5.

135 l'aide du potentiel ~voqu~ somatosensoriel (PES) h partir des membres sup~rieur et inf6rieur et de la d6termination de la vitesse de conduction du nerf sural. Une conduction normale du nerf sural, mais un PES d'amplitude r6duite et de mauvaise d~finition avec des latences normales h la stimulation du nerf p~ron~al 6voquent un pattern de d6g~n~ration du syst~me nerveux central impliquant s~lectivement des axones h parcours centrip+te, h l'int6rieur du fascicule gracile. We are grateful to Dr. P.M. Rossini for his suggestions and valuable criticism.

References

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