Physiological Abnormahties in Hereditary Hyperekplexia Joseph Matsumoto, MD,” Peter Fuhr, MD,” Michael Nigro, MD,? and Mark Hallett, MD”
Five patients from a kindred with hereditary hyperekplexia had physiological testing. The surface-recorded electromyographic pattern of audiogenic muscle jerks was identical to that of the normal acoustic startle reflex. Testing at graded stimulus intensities indicated an increase in the gain of the acoustic startle reflex. Nose-tap stimuli resulted in short-latencygeneralized electromyographicbursts that were similar to the R1 component of the blink reflex. Electrical stimulation of peripheral nerves elicited a pattern of generalized muscle jerks that was similar to that of the acoustic startie reflex. Somatosensory evoked potentials, brainstem auditory evoked potentials, and cortical auditory evoked potentials were normal. The primary physiological abnormality in hereditary hyperekplexia is widespread elevated gain of vestigial withdrawal reflexes in the brainstem and possibly the spinal cord, most likely resulting from increased excitability of reticular neurons. Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol 1992;32:41-50
Hereditary hyperekplexia is a rare autosomal dominant disorder in which unheralded sensory stimuli evoke massive, generalized motor responses. Because of the oumard similarity of this phenomenon to everyday startle, the disorder is also known as “startle disease” or “exaggerated startle.” While the distinctive clinical syndrome of hyperekplexia is well described 11-31, its pathophysiology is controversial. Despite its intuitive designation as “startle disease,” hyperekplexia has no proved relation to the normal human startle response. The pathways of the mammalian acoustic startle reflex reside in the brainstem. In hyperekplectic patients, the electromyographic (EMG) response to acoustic stimulation has an unusually short latency of onset, which suggests that these brainstem pathways may be functioning abnormally E l , 41. Exaggerated head retraction reflexes occurring at extremely short latencies also implicate abnormal or hyperexcitable brainstem reflexes 111. By contrast, other clinical neurophysiological abnormalities implicate the cerebral cortex as a site of increased excitability C2, 4, 51. Wilkins and colleagues [6} reviewed the available physiological data and reached a tentative conclusion that hyperekplexia is a disorder akin to reticular reflex myoclonus. They emphasized that firm conclusions awaited more detailed observations interpreted in light of the growing basic science of the normal startle response in humans and animals.
We made physiological observations on 5 members of a family with hyperekplexia. The objectives were to explore the relation of hyperekplexia to the normal human startle response, to determine whether physiological analysis could isolate the sites of hyperexcitability in hyperekplexia, and to determine whether the disorder has characteristic physiological abnormalities that might serve as a diagnostic test.
From the *Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, and Khildren’s Hospital of Michigan, Wayne State University, Detroit, MI.
Received Sep 25, 1991, and in revised form Dec 9. Accepted for publication Dec 15. 1991.
Patients and Methods We studied 5 patients, aged 2, 3%, 13, 23, and 47 years, from a family with hereditary hyperekplexia. Patients or their guardians gave written informed consent for the study. The protocol was approved by the National Institute of Neurological Disorders and Stroke (NINDS) clinical investigational review committee. The patients’ clinical characteristics (Table 1) were consistent with those described in other clinical studies { l , 2). All patients, except 1, were taking clonazepam during the study. The children continued to take their regular dosage of 1 mg daily. Two adults reduced their daily dosages from 4 and 6 mg to 1 and 2 mg, but were unable to discontinue the drug entirely. The 13-year-old patient discontinued her clonazepam for 2 weeks before testing and was clinically the most severely affected. For purposes of data analysis, she was included in the adult group of patients. Control subjects were healthy, well-rested adult volunteers who were taking no medications. Four (2 men and 2 women, aged 18-42 years) had acoustic startle reflex testing. Eight
iddress correspondence
Dr Hallen, Building Room 5N226, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
Copyright 0 1992 by the American Neurological Association 41
Table 1 . Clinical Characteristics of Patients with Hereditary Hyperekplexia Patient
Age (yr)/Sex
Time of Onset
Infantile Apnea
Excessive Startle
1 2 3 4 5
47/F 23lF 13lF 3.5IF 2/F
Birth Birth Birth Birth Birth
+
+ + + + +
NA
=
-
+ -
Nocturnal Jerks
Response to Nose Tap
Clonazepam
+ + +
+
NA NA
-
+ + + + +
1 mglday 2 mglday 0 mglday 1 mglday 1 mglday
Falls
Stiffness
+ + +
+
+
+
+ +
information not available.
(4 men and 4 women, aged 18-49 years) had reflex testing to nose taps.
Corp, Maynard, MA). Responses to acoustic, somatosensory, and visual stimuli were studied in all patients and control subjects.
Illustrative Case Hbtory Patient 1, a 47-year-old woman, was the product of a normal pregnancy and vaginal delivery. O n the day after birth, she was found cyanotic and stiff in her crib, and an episode of apnea was thought to be the cause. She recovered, but stiffness and exaggerated startle responses were present from then on. She began walking at the age of 3 years, and from the start frequent falling became a problem. The falls, which continued into her adult life, were triggered by a sudden noise, such as ringing of the telephone or a sudden movement. She stiffened and fell, often lacerating her chin or face, as she was unable to make protective movements with her arms. Loss of consciousness did not occur unless the falls were complicated by severe head injury. This startle reaction was accompanied by a sense of surprise, heart palpitations, and momentary confusion. Reactions were more frequent and intense with menstruation, anger, o r anxiety. Although muscle spasms during rest became less severe in early childhood, a sense of muscle stiffness and slow movements persisted and was worsened by cold weather. Spontaneous leg jerking occurred at night and awakened her from sleep, but unprovoked muscle jerking was rare during wakefulness. At one time, the patient was confined to a wheelchair because of frequent falls. Treatment with clonazepam (6 mglday) resulted in marked improvement, and the patient now is able to walk independently. She had bilateral femoral hernias and mild scoliosis. O n examination, she had slow saccadic eye movements, slowing of rapid movements of the hands and fingers, and a slow but not ataxic gait. Tendon reflexes in the legs were mildly increased. Muscle tone was normal. Plantar reflexes were flexor. When the patient was tapped on the nose, her head jerked back rapidly, and the reaction did not appear to diminish on repeated trials.
Electromyographic Re&x Studies Gold disc electrodes were applied in bipolar linkages with 2to 4-cm interelectrode distances over ten muscles of the head, trunk, and limbs. The EMG signals were amplified with a bandwidth of 100 to 1,000 Hz (Grass Neurodata, Grass Instrument Co, Quincy, MA). The signals were digitized at a sampling rate of 2 kHz for 500 msec and stored for later analysis (Neuroscience AVERAGE, version 10.1, Neuroscience Systems, Van Nuys, CA; PDP-11, Digital Equipment
42 Annals of Neurology
Vol 32 No 1 July 1992
Acoustic stimuli consisted of binaural, 1,000-Hz pure tones with zero rise and fall times and a 50-msec plateau (Nicolet, Madison, WI). A maximal stimulus of 103 d B was delivered every 45 to 60 seconds for a total of 20 trials, in order to assess habituation of the response. In addition, graded stimulus intensities ranging from 5 to 103 d B were presented in increments of 4 to 5 dB at 60-second intervals to assess the threshold for the response. In Patient 3 and in the control subjects, 103-dB acoustic stimuli were also given at 10-second intervals for 10 trials, to assess habituation at more rapid stimulus rates. AUDIOGENIC REFLEXES.
SOMATOSENSORY REFLEXES. Square-wave electrical pulses of 0.1-msec duration were delivered to the left median nerve, with the subjects at rest. Stimulus intensities were the lowest that produced a supramaximal M-response. EMG responses to trigeminal stimulation were recorded at a bandwidth of 100 to 5,000 kHz (Dantec 15C01, Dantec Medical, Inc, Santa Clara, CA). Reflexes were elicited with standard electrical stimuli of 0.1-msec duration over the supraorbital nerves or with light taps to the nose, chin, glabella, or supraorbital areas with a triggering hammer (DISA 15B01, Dantec Medical, Inc).
Photic stimuli with a luminescence of 22 lumen seclft’ (Grass PS22, Grass Instrument Co) were presented to the subject’s open eyes in a dark room. VISUAL REFLEXES.
Evoked Potentials and Electroencephalographic Studies Somatosensory evoked potentials to median nerve stimulation were obtained with 1-Hz stimulation at motor threshold. A sampling rate of 2,500 H z was used over a 102-msec period of analysis (Neuroscience AVERAGE, version 10. l). The electroencephalographic (EEG) response to maximal acoustic stimuli was evaluated in both single and averaged tracings. Brainstem auditory evoked potentials to monaural click stimulation at 60 d B SL were obtained with a sampling rate of 14 kHz over an 18-msec period of analysis.
Estimated Spinal Cord Conduction Velocities Efferent spinal cord conduction velocity can be estimated with the assumption that the reflex response of all muscles
tested is generated at the same time and the only difference is the conduction time to those muscles. There is the additional assumption that the central efferent axons to different muscles originate from the same cell bodies or have the same conduction velocity. Efferent spinal cord conduction velocities were estimated by placing surface EMG electrodes over paraspinal muscles at C-5, T-6, and L-1 vertebral levels. The recording montage at each level consisted of electrodes over the spinous process and 2 cm lateral over the adjacent paraspinal muscles. Onset latencies of responses to acoustic, electrical, and nose-tap stimuli were calculated only if a trial had a quiet background and clear EMG onset. Efferent spinal cord conduction velocity was calculated as the difference between the onset latencies from the responses at C-5 and L-1 levels divided by the distance between these points. Afferent spinal cord conduction velocity can be estimated with the assumption that the reflex response to two different stimuli coming in at two different levels of the neuraxis originates at the same place after the same amount of central processing time. Afferent spinal cord conduction could only be estimated for Patient 3, in whom responses to both median and peroneal nerve electrical stimuli were recorded in the orbicularis oculi. H reflexes in thenar and tibialis anterior muscles were evoked during slight voluntary activity. Peripheral conduction times for each nerve were calculated as: (‘(H-reflex latency) - (Distal motor latency) - 1112 The difference in peripheral conduction times for the two nerves was subtracted from the difference in onset latencies of responses in the orbicularisoculi for the two sites of stimulation, to derive the afferent spinal cord conduction time. Afferent cord conduction velocity was estimated as the afferent spinal cord conduction time divided by the distance between the C-8 and L-1 levels.
Needle Electromyographic Studies Standard concentric needle EMG was performed on the deltoid, biceps, first dorsal interosseous, and medial gastrocnemius muscles of the adult patients.
Data Analysis For EMG reflex studies, mean onset latencies of responses were computed from data obtained in only the first five trials to avoid the effects of habituation. Differences in mean onset latencies between patients and control subjects and between different types of stimulation were compared by analysis of variance (ANOVA).Differences in burst durations were analyzed by unpaired t tests. Amplitudes of the surface-recorded EMG responses were measured as the peak amplitude occurring during the first 100 msec of recording for the head, trunk, and arm muscles and during the first 150 msec for the leg muscles in order to exclude more variable voluntary activity. For each muscle, the peak amplitude was normalized to the maximal amplitude occurring during the trials. For many muscles, the maximal amplitude during the trials exceeded the maximal voluntary amplitude.The sum of the ten normalized amplitudes was used as a measure of EMG activity for each response. For all statistical tests, the level of significance was p < 0.05.
Results Azldiogenic Electromyographic Rejex Studies The pattern of EMG responses to 103-dB acoustic stimuli was identical in the adult patients and control subjects. In both groups, the orbicularis oculi invariably responded first, and the other cranial muscles followed in order and frequency of activation. The sternocleidomastoid responded more frequently and generally at an earlier latency than did the orbicularis oris and masseter. When three o r more muscles responded, the second muscle to react was generally the sternocleidomastoid (78% of patient and 62% of control responses), or less frequently, the orbicularis oris (13% of patient and 23% of control responses) or the masseter (9% of patient and 15% of control responses). Responses in the lumbar paraspinal and limb muscles could be elicited in all patients, but were uncommon in the control subjects. In both the patients and the control subjects, the latency of activity in the abductor pollicis brevis was excessively prolonged compared with that of the biceps, given the distance between these two muscles. Mean onset latencies of the EMG responses to 103dB acoustic stimuli were shorter in the adult patients than in the control subjects for every muscle tested (Table 2 ) . The ranges overlapped, however, and the differences were not significant. Onset latencies in the children (Patients 4 and 5 ) were similar to those of the adult patients. The untreated adolescent patient (Patient 3) had the earliest onset latencies for every muscle tested. Burst durations in patients ranged from 5 0 to 400 msec. Burst durations were significantly longer in the adult patients than in the control subjects for the orbicularis oculi (107 versus 64 msec, p = 0.017) and for the sternocleidomastoid (221 versus 58 msec, p < O.OOOl), the two muscles where sufficient observations permitted comparison. Short-term habituation of the acoustic startle response to stimuli spaced 4 5 to 60 seconds apart was observed in both the patients and the control subjects (Fig 1). The control subjects’ responses generally habituated within 3 to 5 trials, whereas those of the patients remained widespread throughout 20 successive trials, and in the untreated patient no clear habituation occurred by our measure of startle amplitude (Fig 2). In this patient, however, there was habituation PO stimuli at 10-second intervals. The patients’ responses to increasing stimulus intensities were significantly more intense than those of the control subjects at any given stimulus intensity ( p < 0.0001, two-factor ANOVA), and the threshold for the startle reaction occurred at a lower decibel level (Fig 3). In the untreated patient, responses were recorded across a wide enough range to permit analysis of the effect of stimulus intensity on EMG onset latencies. In this patient, increasing stimulus intensity was Matsumoto et al: Hereditary Hyperekplexia 43
Table 2. Onset Latency of Ekctmmyographic (EMG) Response of Ten Muscles to 103-dB Acoustic Stimuli
Patients
Control Subjects No. of Responses
No. of
Muscle
Latency (msec)a
Responses
Latency (rnsec)”
28.5 (22-36) 44.2 (34-60) 48.5 (31-68) 44.2 (28-65) 48.4 (42-58) 52.4 (36-73) 60.2 (46-80) 47.4 (36-63) 57.8 (48-84) 63.4 (48-86)
15 12 14 14 10 14 9 11 10 10
31.3 (20-45) 61.2 (53-64) 59.7 (53-64) 64.3 (58-78) 68.0 (60-76)
~~~~~~~
Orbicularisoculi Masseter Orbicularis oris Sternocleidomastoid Biceps Triceps Abductor pollicis brevis Lumbar paraspinal Vastus lateralis Tibialis anterior
17 6 6 10 2
-
-
90.5 (90-91)
2
-
-
-
-
-
-
“Values are the mean (range) of all EMG responses from 3 adult patients or 4 control subjects obtained in the first 5 trials (the maximum number of responses is 15 for patients and 20 for control subjects) for each muscle tested.
~~
lo
c
Hyperekplexia, n=3 0 Controls. n = 4
0
1111111I I
I
I
I
I
0
5
10
15
20
Trial no. Fig I . Short-term habituation of the acoustic startle response in patients with hereditary hyperekplexia and control subjects, plotted for 20 consecutive trials of 103-dB acoustic stimuli presented 45 to 60 seconds apart. Electromyographic (EMG) activity represents the sum ofthe normalized ma3cimul EMG amplitudes o f the ten muscles tested. Error bars indicate 1 standard deviation.
associated with progressive reductions in EMG onset latencies in all ten muscles tested (Fig 4). Second-order polynominal regression was significant in all muscles (p = 0.0001-0.0057).
Somatosensory Electromyographic Re$ex Studies The responses of the patients and control subjects to the nose-tap stimulus were qualitatively different (Table 3). Short-latency (
Orbicularis oculi 110 I-
u Masseter r
2
- 0 2
Orbicularis dris
30
40
50
60
70
80
90
100
110
dB Fig 3. Electromyographic ( E M G ) responses to graded acoustic stimuli (40-1 03 dB) for byperekplectic patients and control subjects. EMG activity represents the sum of the normalized maximal EMG amplitudes of the ten muscles tested. Ewor bars indicate 1 stdndard deviation.
responses markedly diminished or disappeared during sleep, but reappeared immediately on arousal. Similar responses to nose taps were observed in the orbicularis oculi of all control subjects and in the orbicularis oris and cervical paraspinal muscles in 50% of them. When responses occurred in the control subjects, they were of low amplitude and waxed and waned with repeated trials. No responses were observed in the masseter, sternocleidomastoid, dorsal and lumbar paraspinals, or limb muscles of any of the control subjects. In the patients, the pattern of the EMG onset latency to nose taps was significantly different compared with that elicited by 103-dB acoustic stimuli @ < 0.0001, twofactor ANOVA) (Fig 6A). Median nerve shocks elicited EMG responses in 2 patients, and peroneal nerve shocks elicited a response only in Patient 3. The pattern of the EMG response to median nerve stimuli was similar to that elicited by 103-dB acoustic stimuli, and there was no difference in the EMG onset latencies @ < 0.75, ANOVA) (Fig 6B). With both acoustic stimuli and median nerve shocks, an excessively prolonged latency was observed in the activation of the abductor pollicis brevis. In Patient 3, who had EMG responses to all three stimulus modalities, the pattern of cranial muscle activation was nearly identical for acoustic stimuli and median and peroneal nerve shocks. By contrast, the pattern of activation in the limb muscles appeared to be stimulus dependent (Fig 6C), and a significant interaction between muscle site and stimulation type was observed (two-factor ANOVA, p < 0.001). Post hoc analysis revealed significant differences in EMG onset latencies between the different types of stimulation in the ab-
50
P=00057
30
Triceps
Biceps
r
0
P=00023
20
Abductor pollicis brevis 120
Lumbar paraspinal
r-
100
I
60
li;J, I*,
P-O.ow1
40
*&
4 0 6 0 8 0 1 0 0
Vastus lateralis. dB
Tibialis anterior, dB
Fig 4 . Onset latencies (in msec) of electromyographic (EMG) responses t o graded acoustic stimuli (40-103 dB) for Patient 3, an untreated adolescent. The p values on the graphs are for second-order polynomial regression.
ductor pollicis brevis and vastus lateralis (Scheffe’s test,
p < 0.05). Indeed, with peroneal nerve shocks, the vastus lateralis was activated before the arm muscles, a pattern never seen with acoustic stimuli or median nerve shocks. Visual Electromyographic Refex Studies
In all patients, photic stimulation elicited only an isolated response from the orbicularis oculi, with a latency of 47 to 80 msec.
Evoked Potentials a n d Electroencephalographic Studies Somatosensory evoked potentials were normal. For all 5 patients, the mean N17 latency was 17.6 msec and the mean amplitude 1.8 )*V, while the mean P22 latency was 23.2 msec and the mean amplitude 3.4 FV. Matsumoto et al: Hereditary Hyperekplexia
45
Table 3. Onset Latency and Amplitude of Electromyographic (EMG) Responses of Ten Muscles t o a Single Nose-Tap Stimulus Response1 No. of Subjects Muscle
Patients
Orbicularis oculi Orbicularis oris Masseter Trapezius Sternocleidomastoid Cervical paraspinal Dorsal paraspinal Lumbar paraspinal Triceps
313 31 3 313 313 3/3 313 212 113 213
Control Subjects
10.0 (9-1 1) 11.7 (10-18) 15.6 (13-17) 14.1 (11-15) 14.0 (11-16) 12.2 (10-15) 19.4 (18-20) 28.0 (25-33) 25.7 (23-30)
418 018
118 0/8
418 018 018
016 016
Amplitude (p.V)"
Control Subjects
Patients
818
013
Tibialis anterior
Latency (msec)"
12.7 (9-17) 13.9 (13-22)
-
382 167 153 253 213 307 320 260
-
100 -
16
14.3 (12-17)
-
Control Subjects
Patients
175 95
-
20 -
45
-
-
'Values are the mean (range) latency or the mean amplitude of all EMG responses from adult patients or control subjects in each muscle tested.
n
Control
Patient
;
;
1
0
5 g
1
-
1
2
3
4
CR",.I
Muscles
10
30
50
ms
70
90
10
30
50
70
90
ms
Fig 5. Electromyographic (EMG) responses t o a single nose-tap stimulus in an adult with hyperekplexia and a normal control subject. Arrows indicate delivery of the stimulus.
No high-amplitude late components were observed in any patient. Brainstem auditory evoked potentials were also normal. The EEG response to 103-dB acoustic stimuli showed high-amplitude signals 64 to 78 msec after stimulation. In all cases, however, the responses could be related to simultaneous activity in EMG or electrooculogram channels. No spikes or abnormal cerebral activity could be identified in any single trial or on averaged trials. Estimated Spinal Cord Conduction Velocities
Estimated efferent spinal cord conduction velocities for acoustic stimuli ranged from 34 to 133 m/sec (median, 69 m/sec). There was a tendency for lower stimulus intensities to produce lower velocities in the patients (Fig 7). Maximal values for patients ranged from 98 to 133 m/sec. Efferent spinal cord conduction velocities for electrical stimuli could not be calculated, because flexor or other spinal reflexes appeared at times to be the initial paraspinal muscle activity. For nose-tap stim-
46 Annals of Neurology Vol 32 No 1 July 1992
6
8
1 2 3 1 5 6 7 8 9 1 0
-u cmul
m
Muscles
u Leg
1 2 3 4 5 6 1 8 9 1 0
-
u
CI.0l.l
u Am,
Leg
Muscles
Fig 6. Mean relative electromyographic (EMG) onset latencies for the first five responses to different stzmulus modalities. The relative EMG onset latency for each muscle site was defined as the onset latency minus the orbicularis oculi latency for the same response. (A) Responses of Patients 1 through 3 to 103-dB acoustic stimuli and nose tapping. (B)Responses of Patients 2 and 3 to 103-dB acoustic stimuli and median neme shocks. (C) Responses of Patient 3 to 103-dB acoustic stimuli, median nerve shocks, and peroneal newe shocks. Error bars indicate 1 standard deviation. The muscle recordzng sites are: 1 = orbicularis oculi; 2 = masseter; 3 = orbicularis oris: 4 = sternocleidomstoid; 5 = biceps; 6 = triceps; 7 = abductor pollicis brevis; 8 = lumbar paraspinals; 9 = uastus lateralis; 10 = tibialis anterior.
uli, efferent spinal cord conduction velocities ranged from 35 to 78 m/sec (median, 52 m/sec). The estimated afferent spinal cord conduction velocity for electrical stimuli was 107 mhec in Patient 3.
Needle Electromyography The results of needle EMG studies were normal in all adult patients, who had no evidence of fasciculation, continuous activity, or myotonia. Discussion This study offers convincing evidence that an exaggerated acoustic startle response is responsible for the
O
Conductton Velocity
B
O
OPatlent 1 *Patient 2
o
70
75
OPatient 3 0
0
0
0
80
85
90
95
100
105
dB Level
Fig 7. Estimated effewnt spinal cord conduction velocity for the response of 3 patients with hyperekplexia to acoustic stimuli of various intensities.
audiogenic muscle jerks in hyperekplexia. In both the patients and the control subjects, the EMG burst from the orbicularis oculi was the initial and nearly invariant component in both responses. Cranial muscles, most notably the sternocleidomastoid, followed in order and frequency of activation in both groups. Limb muscles were variably activated in the normal startle response, but were much more consistently active in the patients. The latencies to EMG onset were similar in all muscles between groups, although there was a tendency for shorter onset latencies in the patients. Characteristic of the pattern of muscle activation was an excessively delayed onset latency for the abductor pollicis brevis. A recent report on 8 patients with hereditary or symptomatic hyperekplexia [7} came to the same conclusion. The authors found a pattern of muscle activation similar to what is reported here. They noted that the orbicularis oculi activity could often be divided into two bursts and suggested that the first was a normal auditory blink reflex and the second was part of the startle reflex. This assignment led to the result that the sternocleidomastoid muscle was the earliest responder in the startle reflex, and this conclusion was used as further evidence for a bulbospinal motor generator. Combining our findings with current basic knowledge of the acoustic startle response allows one to speculate as to the neuronal localization of the hyperexcitability. Davis and associates 187 mapped the neural substrates of the acoustic startle circuit in rats. In experiments using brain lesions or stimulation, they showed that the shortest latency components of the startle reflex traverse four brainstem nuclei: the ventral cochlear nucleus, the dorsal nucleus of the lateral lemniscus, the nucleus reticularis pontis caudalis, and the cranial and somatic alpha motor neurons. Hyperexcitability at any point in this reflex arc could explain our findings, but the reticular formation seems most probable. The abnormality is unlikely to be located in acoustic sensory neurons, because multimodal sensory input elicits pathological jerks, and brainstem auditory
evoked responses are normal. In addition, habituation, which develops on the sensory side of a reflex arc [7}, could be demonstrated even in the most severely affected patient, albeit at a much less effective level. The patterned motor response in widespread muscles and the absence of marked exaggerated monosynaptic reflexes make alpha motor neuronal hyperexcitability unlikely. It therefore seems likely that the pontomedullary reticular formation is one locus of hyperexcitability in hyperekplexia. By the measure of efferent spinal cord conduction used in this study, the reticular neurons involved in the acoustic startle response in hyperekplexia utilize axons with conduction velocities of 34 to 133 m/sec and with maximal conduction velocities of 76 to 133 m/sec. It is acknowledged that this measure is at best an estimate, because there is a question of whether the same reticular neurons innervate both cervical and lumbar paraspinal muscles. However, on the basis of experimental data, it seems likely that branching reticulospinal axons would be found in the paraspinal regions [1O}. Further, this method is analogous to the one used by Shimamura and coworkers [l If in calculating reticulospinal conduction in animal preparations. Our values do correspond to those reported for single-unit antidromic and orthodromic stimulation of the pontomedullary reticular formation in the cat, which range from 20 to 150 m/sec, with most axons functioning near maximal values of 100 to 130 m/sec [12--141. They also correspond to the conduction velocity of 100 m/sec reported for neurons involved in the acoustic startle response of the cat [l5}. The estimated efferent spinal cord conduction velocities therefore serve as further evidence of involvement of the acoustic startle circuit in hyperekplexia. While there is great similarity in the EMG patterns of hyperekplectic and normal startle responses, there are also quantitative differences, which may explain the pathophysiology in reticular neurons. Suhren and colleagues [l} noted shortened EMG onset latencies of responses to pistol shots in the orbicularis oculi and trapezius muscles of hyperekplectic patients. Our study showed a similar tendency in both cranial and somatic muscles. In the most severely affected patient, we found progressive shortening of EMG onset latencies in all muscles with increasing stimulus intensities. Recruitment of larger alpha motor neurons with faster conducting peripheral axons can not entirely explain this phenomenon, because differences in onset latencies as large as 50 msec occur in muscles with short peripheral segments, such as cranial and paraspinal muscles. Our finding of increasing efferent spinal cord conduction velocities to gradually increasing stimulus intensities supports the hypothesis that central mechanisms are responsible. One possible explanation for this phenomenon is that at higher stimulus intensities, Matsumoto et ak Hereditary Hyperekplexia 47
there is an orderly recruitment of larger reticular neurons with more direct and faster reticulospinal connections. Another possible explanation is that the reticulospinal output is composed of a series of excitatory discharges. At low stimulus intensities, the response results from temporal summation. At higher intensities, the initial excitatory discharges are larger, giving rise to greater early spatial summation and the resultant shorter onset latencies. In the patients, we noted a graded increase in the response to increasing stimulus intensities, as occurs in normal startle, but the response was greater at any given level, and the response threshold was approximately 25 dB lower than that in the control subjects. Hyperekplexia seems to represent heightened gain of the normal startle reflex. The behavior of the acoustic startle response in Patient 3 provides insight into the neural basis for this response in humans. The orbicularis oculi has the lowest threshold and recruits rapidly, reflecting the importance of reflex protective eye closure. The sternocleidomastoid has the second lowest threshold. The excessively long latency of the response from the abductor pollis brevis may represent a high threshold of neurons involved in the activation of this muscle. However, even at near-maximal recruitment, the response from the abductor pollicis brevis is 20 msec longer than that from the triceps or biceps. An additional factor may be that smaller, slower-conducting reticulospinal axons innervate abductor pollicis brevis motor neurons in a manner consistent with the known axial predominance of the reticulospinal tract. The nature of the motor response is thus determined by the differential thresholds and shapes of the recruitment curves. The reflex myoclonic jerk in response to nose tapping is a characteristic abnormality in hyperekplexia 116, 17). Andermann and coauthors 1181 reported associated EMG bursts in the limbs at latencies shorter than those elicited by sound. In our hyperekplectic patients, short-duration EMG bursts with extremely short onset latencies were noted in cranial, spinal, and limb muscles. The abnormal response is similar in latency to the R1 component of the blink reflex, which is mediated by an oligosynaptic pathway comprising the trigeminal neuron, a reticular neuron, and the facial motor neuron C19). The more variable R2 late response is a polysynaptic pathway involving a greater number of intervening pontomedullary reticular neurons. By arguments similar to those presented earlier, we believe that the locus of excitability in this manifestation of hyperekplexia lies within the reticular formation, but it seems that a different pathway is involved. The EMG bursts in response to nose tapping are much less variable and of shorter duration than those involved in the acoustic startle response. In addition, they are less prone to habituation, and the order of activation of the muscles in relation to the orbicularis 48 Annals of Neurology Vol 32 No 1 July 1992
oculi is different from that evoked by noise. We hypothesize that patients with hyperekplexia exhibit generdzed R1-like motor reflexes to this type of trigeminal stimulation. Scheibel and associates 120) identified bulbar reticular neurons that were selectively driven by nose pressure in the cat. Such neurons may organize a primitive oligosynaptic withdrawal reflex, which is unmasked in hyperekplexia. Brown and coworkers 177 also studied responses to taps in the “mantle area.” They suggested that the early response in the orbicularis oculi was normal and that the later activity characterized the startle reflex. Looked at in this way, the sternocleidomastoid muscle was the earliest activated, and the full pattern of muscle activation was sufficiently similar to the acoustic startle reflex that the two reflexes were considered the same. Further work will be necessary to resolve this difference in interpretation. Electrical stimuli elicited generalized motor responses in 2 patients, and 1 patient demonstrated responses to both median and peroneal nerve stimulation. The pattern of these responses was different from those elicited by acoustic or trigeminal stimulation. In the cranial musculature, the EMG activation appeared similar to that evoked by acoustic stimuli, which suggests that somatosensory stimuli from the limbs project to the same polysynaptic pontomedullary reticular pathways as acoustic stimuli. In the leg, however, the pattern was unique, with EMG activation in the stimulated leg occurring earlier than would be expected in the acoustic startle response. The pattern of activation with peroneal nerve stimulation was identical to that observed with high-frequency plantar stimulation delivered in a manner described for stimulation of the flexor reflex 121). Although we have no comparative normative data, flexor responses are reported as being uncommon to single shocks and are of low amplitude when present [2 13. This raises the possibility that spinal neurons within the flexor reflex chain are also hyperexcitable in hyperekplexia. Our median values of 69 m/sec for the efferent spinal cord conduction velocity to acous*ic stimuli and 107 m/sec for afferent spinal cord conduction velocity to somatosensory stimuli differ from those for the spinobulbospinal reflex reported in dogs and monkeys [l 11, in which the efferent velocity is 30 m/sec and the afferent velocity is 60 m/sec. However, the relative conduction velocities are preserved, with afferent conduction being approximately twice as fast as efferent conduction 111). Karpukhina and colleagues 122) found that nocioceptive stimuli activated medullary reticular neurons with axonal conduction velocities of approximately 3 3 m/sec. Non-nocioceptive stimuli, on the other hand, more selectively activated reticular neurons within the nucleus reticularis pontis caudalis with faster axonal conduction velocities of approximately 84 m/sec. Our values may reflect hyperexcit-
ability in this latter circuit rather than the classic spinobulbospinal reflex. Photic stimulation was ineffective in producing generahzed startle responses in the patients despite their complaints of jerks to sudden nearby movements. It is possible that the noise accompanying such movements, rather than the visual stimulus itself, triggers the startle response. The most prominent physiological abnormality in hereditary hyperekplexia is a lowered threshold in pontomedullary reticular neurons, resulting in an increased gain of a number of vestigial reflexes, all of which are present to a lesser degree in normal subjects. Hereditary hyperekplexia thus represents a specific reticular reflex disorder. Current evidence divides the brainstem reticular formation into discrete nuclei with specific input-output relationships I231. The reticular formation acts to regulate the gain between sensory input and motor, autonomic, and ascending output I241. A patient with reticular reflex myoclonus secondary to anoxia, described by Hallett and coauthors 1251, had brief, short-latency EMG bursts occurring predominantly with limb stimulation, as well as EEG spikes appearing with variable latencies following the myoclonus. It seems clear that the gain of specific reticular reflexes was increased in this patient, but in a different manner than in those with hereditary hyperekplexia, in which burst durations are longer and trigeminal and acoustic stimulation is most effective. It is anticipated that future studies will identify a variety of reticular reflex disorders. Our data suggest that hereditary hyperekplexia may involve spinal as well as brainstem hyperexcitability. Because the reticular formation is a rostral extension of the spinal gray matter, such an overlap would not be unexpected. Spinal hyperexcitability could explain the spasticity, hyperreflexia, and muscle stiffness seen in some patients with hyperekplexia, as well as the features of hyperekplexia seen in some patients with stiff-man syndrome E261. The widespread nature of hyperexcitability in hyperekplexia is extended further by the reports of abnormal EEG activity and enlarged somatosensory evoked potentials 12, 51. Because our patients did not exhibit cortical abnormalities, it appears that this is a variable manifestation of the disease. A genetic error in a common neurochemical system (such as the gamma-aminobutyric acid system) could explain the widespread physiological abnormalities. Because hyperekplexia represents an exaggeration of normal withdrawal reflexes, it is unlikely that any single electrophysiological test could clearly separate mildly affected patients from unaffected subjects. The finding in an adult of short-latency EMG bursts in the limb, lower paraspinal, and sternocleidomastoid muscles to nose tapping is sufficiently unusual to be supportive of the diagnosis. The soecificity for hyperek-
plexia is not established, however. The issue of these trigeminomotor reflexes in normal newborns or children has not been addressed, and the value of this test in pediatric hyperekplexia is undefined. The topic may warrant further investigation given the known association of hyperekplexia with the sudden infant death syndrome 127).
We thank B. J. Hessie for editorial assistance.
References 1. Suhren 0, Bruyn GW, Tuynman JA. Hyperexplexia: a hereditary startle syndrome. J Neurol Sci 1966;3:575-605 2. Andermann F, Keene DL, Andermann E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain 1980;103:985-997 3. Saenz-Lope E, Herranz-Tanarro FJ, Masdeu JC, Chacon Pena JR. Hyperekplexia: a syndrome of pathological startle responses. Ann Neurol 1984;15:36-41 4. Gastaut H, Villeneuve A. The startle disease or hyperekplexia: pathological surprise reaction. J Neurol Sci 1967;5:523-542 5. Markand ON, Garg BP, Weaver DD. Familial startle disease (hyperexplexia): electrophysiologic studies. Arch Neurol 1984; 4 1:7 1-74 6. Wilkins DE, Hallett M, Wess MM. Audiogenic startle reflex of man and its relationship to startle syndromes: a review. Brain 1986;109~56 1-573 7. Brown P, Rothwell JC, Thompson PD, et al. The hyperekplexias and their relationship to the normal startle reflex. Brain 1991;114:1903-1928 8. Davis M, Gendelman DS, Tischler MD, Gendelman PM. A primary acoustic startle circuit: lesion and stimulation studies. J Neurosci 1982;2:791-805 9. Davis M, Parisi T, Gendelman DS, et al. Habituation and sensitization of startle reflexes elicited electrically from the brainstem. Science 1982;218:689-690 10. Peterson BW, Pitts NG, Fukushima K. Patterns of projection and branching of reticdospinal neurons. Exp Brain Res 1975; 23:333-351 11. Shimamura M, Mori S, Matsushima S, Fujimora B. On the spino-bulbo-spinal reflex in dogs, monkeys, and man. Jpn J Physiol 1964;14:411-421 12. It0 M, Udo M, Mano N. Long inhibitory and excitatory pathways converging onto cat reticular and Deiter's neurons and their relevance to reticdofugal axons. J Neurophysiol 1970; 33:210-226 13. Wilson VJ, Yoshida M, Schor RH. Supraspinal excitation and inhibition of thoracic back motoneurons. Exp Brain Res 1970; 11~282-295 14. Eccles JC, Nicoll RA, Schwarz DWF, et al. Reticdospinal neurons with and without monosynaptic . - inputs from cerebellar nuclei. J Neurophysiol 1975;38:513-530 15. Wu MF, Suzuki SS, Siege1JM. Anatomical distribution and response patterns of reticular neurons active in relation to acoustic startle. Brain Res 1988;457:399-406 16. Kurczynski "W. Hyperekplexia Arch Neurol 1983;40246248 17. Andermann F, Andermann E. Startle disorders of man: hyperekplexia, jumping and startle epilepsy. Brain Dev 1988;lO: 2 13-222 18. Andermann F. Andermann E. Gendron D. Startle disease (hy-
Matsumoto et ai: Hereditary Hyperekplexia 49
19.
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perekplexia): a hereditary disorder with abnormal startle, falling spells, and attacks of spontaneous clonus. Cleve Clin J Med 1990;5?(~~ppl):S54-S60 hag& M, Takeshita K, Nakao S, et al. An electrophysiologically defined trigemino-reticulo-facial pathway related to the blink reflex in the cat. Neurosci Lett 1989;96:64-69 Scheibel M, Scheibel A, Mollica A, Moruzzi G. Convergence and interaction of afferent impulses on single units of reticular formation. J Neurophysiol 1955;8:309-33 1 Meinck HM, Kuster S, Benecke R, Conrad B. The flexor reflex: influence of stimulus parameters on the reflex response. Electroencephalogr Clin Neurophysiol 1985;61:287-298 Karpukhina MV, Gokin AP, Limanskii YP. Activation of pontine and bulbar reticulo-spinal neurons in the cat by somatosensory stimuli of different modalities. Neurophysiology [Neirofiziologiya] 1986;18:461-469
50 Annals of Neurology Vol 32 No 1 July 1992
23. Newman DB, Hilleary SK, Ginsberg CY. Nuclear terminations of corticoreticular fiber systems in rats. Brain Behav Evol 1989;34:223-264 24. Chase MH. The motor functions of the reticular formation are multifaceted and state-determined. In: Hobson JA, Brazier MAB, eds. The reticular formation revisited. New York: Raven Press, 1980:449-4 72 25. Hallett M, Chadwick D, Adam J, Marsden CD. Reticular reflex myoclonus: a physiological type of human post-hypoxic myoclonus. J Neurol Neurosurg Psychiatry 197?;40:253-264 26. Leigh PN, Rothweli JC, Traub M, Marsden CD. A patient with reflex myoclonus and muscle rigidity: “jerking stiff-man syndrome.” J Neurol Neurosurg Psychiatry 1980;43:1125-1131 27. Vigevano F, DiCapua M, Dalla Bernardina B. Startle disease: an avoidable cause of sudden infant death. Lancet 1989;1:216 (Letter to the editor)
Five patients from a kindred with hereditary hyperekplexia had physiological testing. The surface-recorded electromyographic pattern of audiogenic muscle jerks was identical to that of the normal acoustic startle reflex. Testing at graded stimulus intensities indicated an increase in the gain of the acoustic startle reflex. Nose-tap stimuli resulted in short-latencygeneralized electromyographicbursts that were similar to the R1 component of the blink reflex. Electrical stimulation of peripheral nerves elicited a pattern of generalized muscle jerks that was similar to that of the acoustic startie reflex. Somatosensory evoked potentials, brainstem auditory evoked potentials, and cortical auditory evoked potentials were normal. The primary physiological abnormality in hereditary hyperekplexia is widespread elevated gain of vestigial withdrawal reflexes in the brainstem and possibly the spinal cord, most likely resulting from increased excitability of reticular neurons. Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol 1992;32:41-50
Hereditary hyperekplexia is a rare autosomal dominant disorder in which unheralded sensory stimuli evoke massive, generalized motor responses. Because of the oumard similarity of this phenomenon to everyday startle, the disorder is also known as “startle disease” or “exaggerated startle.” While the distinctive clinical syndrome of hyperekplexia is well described 11-31, its pathophysiology is controversial. Despite its intuitive designation as “startle disease,” hyperekplexia has no proved relation to the normal human startle response. The pathways of the mammalian acoustic startle reflex reside in the brainstem. In hyperekplectic patients, the electromyographic (EMG) response to acoustic stimulation has an unusually short latency of onset, which suggests that these brainstem pathways may be functioning abnormally E l , 41. Exaggerated head retraction reflexes occurring at extremely short latencies also implicate abnormal or hyperexcitable brainstem reflexes 111. By contrast, other clinical neurophysiological abnormalities implicate the cerebral cortex as a site of increased excitability C2, 4, 51. Wilkins and colleagues [6} reviewed the available physiological data and reached a tentative conclusion that hyperekplexia is a disorder akin to reticular reflex myoclonus. They emphasized that firm conclusions awaited more detailed observations interpreted in light of the growing basic science of the normal startle response in humans and animals.
We made physiological observations on 5 members of a family with hyperekplexia. The objectives were to explore the relation of hyperekplexia to the normal human startle response, to determine whether physiological analysis could isolate the sites of hyperexcitability in hyperekplexia, and to determine whether the disorder has characteristic physiological abnormalities that might serve as a diagnostic test.
From the *Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, and Khildren’s Hospital of Michigan, Wayne State University, Detroit, MI.
Received Sep 25, 1991, and in revised form Dec 9. Accepted for publication Dec 15. 1991.
Patients and Methods We studied 5 patients, aged 2, 3%, 13, 23, and 47 years, from a family with hereditary hyperekplexia. Patients or their guardians gave written informed consent for the study. The protocol was approved by the National Institute of Neurological Disorders and Stroke (NINDS) clinical investigational review committee. The patients’ clinical characteristics (Table 1) were consistent with those described in other clinical studies { l , 2). All patients, except 1, were taking clonazepam during the study. The children continued to take their regular dosage of 1 mg daily. Two adults reduced their daily dosages from 4 and 6 mg to 1 and 2 mg, but were unable to discontinue the drug entirely. The 13-year-old patient discontinued her clonazepam for 2 weeks before testing and was clinically the most severely affected. For purposes of data analysis, she was included in the adult group of patients. Control subjects were healthy, well-rested adult volunteers who were taking no medications. Four (2 men and 2 women, aged 18-42 years) had acoustic startle reflex testing. Eight
iddress correspondence
Dr Hallen, Building Room 5N226, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
Copyright 0 1992 by the American Neurological Association 41
Table 1 . Clinical Characteristics of Patients with Hereditary Hyperekplexia Patient
Age (yr)/Sex
Time of Onset
Infantile Apnea
Excessive Startle
1 2 3 4 5
47/F 23lF 13lF 3.5IF 2/F
Birth Birth Birth Birth Birth
+
+ + + + +
NA
=
-
+ -
Nocturnal Jerks
Response to Nose Tap
Clonazepam
+ + +
+
NA NA
-
+ + + + +
1 mglday 2 mglday 0 mglday 1 mglday 1 mglday
Falls
Stiffness
+ + +
+
+
+
+ +
information not available.
(4 men and 4 women, aged 18-49 years) had reflex testing to nose taps.
Corp, Maynard, MA). Responses to acoustic, somatosensory, and visual stimuli were studied in all patients and control subjects.
Illustrative Case Hbtory Patient 1, a 47-year-old woman, was the product of a normal pregnancy and vaginal delivery. O n the day after birth, she was found cyanotic and stiff in her crib, and an episode of apnea was thought to be the cause. She recovered, but stiffness and exaggerated startle responses were present from then on. She began walking at the age of 3 years, and from the start frequent falling became a problem. The falls, which continued into her adult life, were triggered by a sudden noise, such as ringing of the telephone or a sudden movement. She stiffened and fell, often lacerating her chin or face, as she was unable to make protective movements with her arms. Loss of consciousness did not occur unless the falls were complicated by severe head injury. This startle reaction was accompanied by a sense of surprise, heart palpitations, and momentary confusion. Reactions were more frequent and intense with menstruation, anger, o r anxiety. Although muscle spasms during rest became less severe in early childhood, a sense of muscle stiffness and slow movements persisted and was worsened by cold weather. Spontaneous leg jerking occurred at night and awakened her from sleep, but unprovoked muscle jerking was rare during wakefulness. At one time, the patient was confined to a wheelchair because of frequent falls. Treatment with clonazepam (6 mglday) resulted in marked improvement, and the patient now is able to walk independently. She had bilateral femoral hernias and mild scoliosis. O n examination, she had slow saccadic eye movements, slowing of rapid movements of the hands and fingers, and a slow but not ataxic gait. Tendon reflexes in the legs were mildly increased. Muscle tone was normal. Plantar reflexes were flexor. When the patient was tapped on the nose, her head jerked back rapidly, and the reaction did not appear to diminish on repeated trials.
Electromyographic Re&x Studies Gold disc electrodes were applied in bipolar linkages with 2to 4-cm interelectrode distances over ten muscles of the head, trunk, and limbs. The EMG signals were amplified with a bandwidth of 100 to 1,000 Hz (Grass Neurodata, Grass Instrument Co, Quincy, MA). The signals were digitized at a sampling rate of 2 kHz for 500 msec and stored for later analysis (Neuroscience AVERAGE, version 10.1, Neuroscience Systems, Van Nuys, CA; PDP-11, Digital Equipment
42 Annals of Neurology
Vol 32 No 1 July 1992
Acoustic stimuli consisted of binaural, 1,000-Hz pure tones with zero rise and fall times and a 50-msec plateau (Nicolet, Madison, WI). A maximal stimulus of 103 d B was delivered every 45 to 60 seconds for a total of 20 trials, in order to assess habituation of the response. In addition, graded stimulus intensities ranging from 5 to 103 d B were presented in increments of 4 to 5 dB at 60-second intervals to assess the threshold for the response. In Patient 3 and in the control subjects, 103-dB acoustic stimuli were also given at 10-second intervals for 10 trials, to assess habituation at more rapid stimulus rates. AUDIOGENIC REFLEXES.
SOMATOSENSORY REFLEXES. Square-wave electrical pulses of 0.1-msec duration were delivered to the left median nerve, with the subjects at rest. Stimulus intensities were the lowest that produced a supramaximal M-response. EMG responses to trigeminal stimulation were recorded at a bandwidth of 100 to 5,000 kHz (Dantec 15C01, Dantec Medical, Inc, Santa Clara, CA). Reflexes were elicited with standard electrical stimuli of 0.1-msec duration over the supraorbital nerves or with light taps to the nose, chin, glabella, or supraorbital areas with a triggering hammer (DISA 15B01, Dantec Medical, Inc).
Photic stimuli with a luminescence of 22 lumen seclft’ (Grass PS22, Grass Instrument Co) were presented to the subject’s open eyes in a dark room. VISUAL REFLEXES.
Evoked Potentials and Electroencephalographic Studies Somatosensory evoked potentials to median nerve stimulation were obtained with 1-Hz stimulation at motor threshold. A sampling rate of 2,500 H z was used over a 102-msec period of analysis (Neuroscience AVERAGE, version 10. l). The electroencephalographic (EEG) response to maximal acoustic stimuli was evaluated in both single and averaged tracings. Brainstem auditory evoked potentials to monaural click stimulation at 60 d B SL were obtained with a sampling rate of 14 kHz over an 18-msec period of analysis.
Estimated Spinal Cord Conduction Velocities Efferent spinal cord conduction velocity can be estimated with the assumption that the reflex response of all muscles
tested is generated at the same time and the only difference is the conduction time to those muscles. There is the additional assumption that the central efferent axons to different muscles originate from the same cell bodies or have the same conduction velocity. Efferent spinal cord conduction velocities were estimated by placing surface EMG electrodes over paraspinal muscles at C-5, T-6, and L-1 vertebral levels. The recording montage at each level consisted of electrodes over the spinous process and 2 cm lateral over the adjacent paraspinal muscles. Onset latencies of responses to acoustic, electrical, and nose-tap stimuli were calculated only if a trial had a quiet background and clear EMG onset. Efferent spinal cord conduction velocity was calculated as the difference between the onset latencies from the responses at C-5 and L-1 levels divided by the distance between these points. Afferent spinal cord conduction velocity can be estimated with the assumption that the reflex response to two different stimuli coming in at two different levels of the neuraxis originates at the same place after the same amount of central processing time. Afferent spinal cord conduction could only be estimated for Patient 3, in whom responses to both median and peroneal nerve electrical stimuli were recorded in the orbicularis oculi. H reflexes in thenar and tibialis anterior muscles were evoked during slight voluntary activity. Peripheral conduction times for each nerve were calculated as: (‘(H-reflex latency) - (Distal motor latency) - 1112 The difference in peripheral conduction times for the two nerves was subtracted from the difference in onset latencies of responses in the orbicularisoculi for the two sites of stimulation, to derive the afferent spinal cord conduction time. Afferent cord conduction velocity was estimated as the afferent spinal cord conduction time divided by the distance between the C-8 and L-1 levels.
Needle Electromyographic Studies Standard concentric needle EMG was performed on the deltoid, biceps, first dorsal interosseous, and medial gastrocnemius muscles of the adult patients.
Data Analysis For EMG reflex studies, mean onset latencies of responses were computed from data obtained in only the first five trials to avoid the effects of habituation. Differences in mean onset latencies between patients and control subjects and between different types of stimulation were compared by analysis of variance (ANOVA).Differences in burst durations were analyzed by unpaired t tests. Amplitudes of the surface-recorded EMG responses were measured as the peak amplitude occurring during the first 100 msec of recording for the head, trunk, and arm muscles and during the first 150 msec for the leg muscles in order to exclude more variable voluntary activity. For each muscle, the peak amplitude was normalized to the maximal amplitude occurring during the trials. For many muscles, the maximal amplitude during the trials exceeded the maximal voluntary amplitude.The sum of the ten normalized amplitudes was used as a measure of EMG activity for each response. For all statistical tests, the level of significance was p < 0.05.
Results Azldiogenic Electromyographic Rejex Studies The pattern of EMG responses to 103-dB acoustic stimuli was identical in the adult patients and control subjects. In both groups, the orbicularis oculi invariably responded first, and the other cranial muscles followed in order and frequency of activation. The sternocleidomastoid responded more frequently and generally at an earlier latency than did the orbicularis oris and masseter. When three o r more muscles responded, the second muscle to react was generally the sternocleidomastoid (78% of patient and 62% of control responses), or less frequently, the orbicularis oris (13% of patient and 23% of control responses) or the masseter (9% of patient and 15% of control responses). Responses in the lumbar paraspinal and limb muscles could be elicited in all patients, but were uncommon in the control subjects. In both the patients and the control subjects, the latency of activity in the abductor pollicis brevis was excessively prolonged compared with that of the biceps, given the distance between these two muscles. Mean onset latencies of the EMG responses to 103dB acoustic stimuli were shorter in the adult patients than in the control subjects for every muscle tested (Table 2 ) . The ranges overlapped, however, and the differences were not significant. Onset latencies in the children (Patients 4 and 5 ) were similar to those of the adult patients. The untreated adolescent patient (Patient 3) had the earliest onset latencies for every muscle tested. Burst durations in patients ranged from 5 0 to 400 msec. Burst durations were significantly longer in the adult patients than in the control subjects for the orbicularis oculi (107 versus 64 msec, p = 0.017) and for the sternocleidomastoid (221 versus 58 msec, p < O.OOOl), the two muscles where sufficient observations permitted comparison. Short-term habituation of the acoustic startle response to stimuli spaced 4 5 to 60 seconds apart was observed in both the patients and the control subjects (Fig 1). The control subjects’ responses generally habituated within 3 to 5 trials, whereas those of the patients remained widespread throughout 20 successive trials, and in the untreated patient no clear habituation occurred by our measure of startle amplitude (Fig 2). In this patient, however, there was habituation PO stimuli at 10-second intervals. The patients’ responses to increasing stimulus intensities were significantly more intense than those of the control subjects at any given stimulus intensity ( p < 0.0001, two-factor ANOVA), and the threshold for the startle reaction occurred at a lower decibel level (Fig 3). In the untreated patient, responses were recorded across a wide enough range to permit analysis of the effect of stimulus intensity on EMG onset latencies. In this patient, increasing stimulus intensity was Matsumoto et al: Hereditary Hyperekplexia 43
Table 2. Onset Latency of Ekctmmyographic (EMG) Response of Ten Muscles to 103-dB Acoustic Stimuli
Patients
Control Subjects No. of Responses
No. of
Muscle
Latency (msec)a
Responses
Latency (rnsec)”
28.5 (22-36) 44.2 (34-60) 48.5 (31-68) 44.2 (28-65) 48.4 (42-58) 52.4 (36-73) 60.2 (46-80) 47.4 (36-63) 57.8 (48-84) 63.4 (48-86)
15 12 14 14 10 14 9 11 10 10
31.3 (20-45) 61.2 (53-64) 59.7 (53-64) 64.3 (58-78) 68.0 (60-76)
~~~~~~~
Orbicularisoculi Masseter Orbicularis oris Sternocleidomastoid Biceps Triceps Abductor pollicis brevis Lumbar paraspinal Vastus lateralis Tibialis anterior
17 6 6 10 2
-
-
90.5 (90-91)
2
-
-
-
-
-
-
“Values are the mean (range) of all EMG responses from 3 adult patients or 4 control subjects obtained in the first 5 trials (the maximum number of responses is 15 for patients and 20 for control subjects) for each muscle tested.
~~
lo
c
Hyperekplexia, n=3 0 Controls. n = 4
0
1111111I I
I
I
I
I
0
5
10
15
20
Trial no. Fig I . Short-term habituation of the acoustic startle response in patients with hereditary hyperekplexia and control subjects, plotted for 20 consecutive trials of 103-dB acoustic stimuli presented 45 to 60 seconds apart. Electromyographic (EMG) activity represents the sum ofthe normalized ma3cimul EMG amplitudes o f the ten muscles tested. Error bars indicate 1 standard deviation.
associated with progressive reductions in EMG onset latencies in all ten muscles tested (Fig 4). Second-order polynominal regression was significant in all muscles (p = 0.0001-0.0057).
Somatosensory Electromyographic Re$ex Studies The responses of the patients and control subjects to the nose-tap stimulus were qualitatively different (Table 3). Short-latency (
Orbicularis oculi 110 I-
u Masseter r
2
- 0 2
Orbicularis dris
30
40
50
60
70
80
90
100
110
dB Fig 3. Electromyographic ( E M G ) responses to graded acoustic stimuli (40-1 03 dB) for byperekplectic patients and control subjects. EMG activity represents the sum of the normalized maximal EMG amplitudes of the ten muscles tested. Ewor bars indicate 1 stdndard deviation.
responses markedly diminished or disappeared during sleep, but reappeared immediately on arousal. Similar responses to nose taps were observed in the orbicularis oculi of all control subjects and in the orbicularis oris and cervical paraspinal muscles in 50% of them. When responses occurred in the control subjects, they were of low amplitude and waxed and waned with repeated trials. No responses were observed in the masseter, sternocleidomastoid, dorsal and lumbar paraspinals, or limb muscles of any of the control subjects. In the patients, the pattern of the EMG onset latency to nose taps was significantly different compared with that elicited by 103-dB acoustic stimuli @ < 0.0001, twofactor ANOVA) (Fig 6A). Median nerve shocks elicited EMG responses in 2 patients, and peroneal nerve shocks elicited a response only in Patient 3. The pattern of the EMG response to median nerve stimuli was similar to that elicited by 103-dB acoustic stimuli, and there was no difference in the EMG onset latencies @ < 0.75, ANOVA) (Fig 6B). With both acoustic stimuli and median nerve shocks, an excessively prolonged latency was observed in the activation of the abductor pollicis brevis. In Patient 3, who had EMG responses to all three stimulus modalities, the pattern of cranial muscle activation was nearly identical for acoustic stimuli and median and peroneal nerve shocks. By contrast, the pattern of activation in the limb muscles appeared to be stimulus dependent (Fig 6C), and a significant interaction between muscle site and stimulation type was observed (two-factor ANOVA, p < 0.001). Post hoc analysis revealed significant differences in EMG onset latencies between the different types of stimulation in the ab-
50
P=00057
30
Triceps
Biceps
r
0
P=00023
20
Abductor pollicis brevis 120
Lumbar paraspinal
r-
100
I
60
li;J, I*,
P-O.ow1
40
*&
4 0 6 0 8 0 1 0 0
Vastus lateralis. dB
Tibialis anterior, dB
Fig 4 . Onset latencies (in msec) of electromyographic (EMG) responses t o graded acoustic stimuli (40-103 dB) for Patient 3, an untreated adolescent. The p values on the graphs are for second-order polynomial regression.
ductor pollicis brevis and vastus lateralis (Scheffe’s test,
p < 0.05). Indeed, with peroneal nerve shocks, the vastus lateralis was activated before the arm muscles, a pattern never seen with acoustic stimuli or median nerve shocks. Visual Electromyographic Refex Studies
In all patients, photic stimulation elicited only an isolated response from the orbicularis oculi, with a latency of 47 to 80 msec.
Evoked Potentials a n d Electroencephalographic Studies Somatosensory evoked potentials were normal. For all 5 patients, the mean N17 latency was 17.6 msec and the mean amplitude 1.8 )*V, while the mean P22 latency was 23.2 msec and the mean amplitude 3.4 FV. Matsumoto et al: Hereditary Hyperekplexia
45
Table 3. Onset Latency and Amplitude of Electromyographic (EMG) Responses of Ten Muscles t o a Single Nose-Tap Stimulus Response1 No. of Subjects Muscle
Patients
Orbicularis oculi Orbicularis oris Masseter Trapezius Sternocleidomastoid Cervical paraspinal Dorsal paraspinal Lumbar paraspinal Triceps
313 31 3 313 313 3/3 313 212 113 213
Control Subjects
10.0 (9-1 1) 11.7 (10-18) 15.6 (13-17) 14.1 (11-15) 14.0 (11-16) 12.2 (10-15) 19.4 (18-20) 28.0 (25-33) 25.7 (23-30)
418 018
118 0/8
418 018 018
016 016
Amplitude (p.V)"
Control Subjects
Patients
818
013
Tibialis anterior
Latency (msec)"
12.7 (9-17) 13.9 (13-22)
-
382 167 153 253 213 307 320 260
-
100 -
16
14.3 (12-17)
-
Control Subjects
Patients
175 95
-
20 -
45
-
-
'Values are the mean (range) latency or the mean amplitude of all EMG responses from adult patients or control subjects in each muscle tested.
n
Control
Patient
;
;
1
0
5 g
1
-
1
2
3
4
CR",.I
Muscles
10
30
50
ms
70
90
10
30
50
70
90
ms
Fig 5. Electromyographic (EMG) responses t o a single nose-tap stimulus in an adult with hyperekplexia and a normal control subject. Arrows indicate delivery of the stimulus.
No high-amplitude late components were observed in any patient. Brainstem auditory evoked potentials were also normal. The EEG response to 103-dB acoustic stimuli showed high-amplitude signals 64 to 78 msec after stimulation. In all cases, however, the responses could be related to simultaneous activity in EMG or electrooculogram channels. No spikes or abnormal cerebral activity could be identified in any single trial or on averaged trials. Estimated Spinal Cord Conduction Velocities
Estimated efferent spinal cord conduction velocities for acoustic stimuli ranged from 34 to 133 m/sec (median, 69 m/sec). There was a tendency for lower stimulus intensities to produce lower velocities in the patients (Fig 7). Maximal values for patients ranged from 98 to 133 m/sec. Efferent spinal cord conduction velocities for electrical stimuli could not be calculated, because flexor or other spinal reflexes appeared at times to be the initial paraspinal muscle activity. For nose-tap stim-
46 Annals of Neurology Vol 32 No 1 July 1992
6
8
1 2 3 1 5 6 7 8 9 1 0
-u cmul
m
Muscles
u Leg
1 2 3 4 5 6 1 8 9 1 0
-
u
CI.0l.l
u Am,
Leg
Muscles
Fig 6. Mean relative electromyographic (EMG) onset latencies for the first five responses to different stzmulus modalities. The relative EMG onset latency for each muscle site was defined as the onset latency minus the orbicularis oculi latency for the same response. (A) Responses of Patients 1 through 3 to 103-dB acoustic stimuli and nose tapping. (B)Responses of Patients 2 and 3 to 103-dB acoustic stimuli and median neme shocks. (C) Responses of Patient 3 to 103-dB acoustic stimuli, median nerve shocks, and peroneal newe shocks. Error bars indicate 1 standard deviation. The muscle recordzng sites are: 1 = orbicularis oculi; 2 = masseter; 3 = orbicularis oris: 4 = sternocleidomstoid; 5 = biceps; 6 = triceps; 7 = abductor pollicis brevis; 8 = lumbar paraspinals; 9 = uastus lateralis; 10 = tibialis anterior.
uli, efferent spinal cord conduction velocities ranged from 35 to 78 m/sec (median, 52 m/sec). The estimated afferent spinal cord conduction velocity for electrical stimuli was 107 mhec in Patient 3.
Needle Electromyography The results of needle EMG studies were normal in all adult patients, who had no evidence of fasciculation, continuous activity, or myotonia. Discussion This study offers convincing evidence that an exaggerated acoustic startle response is responsible for the
O
Conductton Velocity
B
O
OPatlent 1 *Patient 2
o
70
75
OPatient 3 0
0
0
0
80
85
90
95
100
105
dB Level
Fig 7. Estimated effewnt spinal cord conduction velocity for the response of 3 patients with hyperekplexia to acoustic stimuli of various intensities.
audiogenic muscle jerks in hyperekplexia. In both the patients and the control subjects, the EMG burst from the orbicularis oculi was the initial and nearly invariant component in both responses. Cranial muscles, most notably the sternocleidomastoid, followed in order and frequency of activation in both groups. Limb muscles were variably activated in the normal startle response, but were much more consistently active in the patients. The latencies to EMG onset were similar in all muscles between groups, although there was a tendency for shorter onset latencies in the patients. Characteristic of the pattern of muscle activation was an excessively delayed onset latency for the abductor pollicis brevis. A recent report on 8 patients with hereditary or symptomatic hyperekplexia [7} came to the same conclusion. The authors found a pattern of muscle activation similar to what is reported here. They noted that the orbicularis oculi activity could often be divided into two bursts and suggested that the first was a normal auditory blink reflex and the second was part of the startle reflex. This assignment led to the result that the sternocleidomastoid muscle was the earliest responder in the startle reflex, and this conclusion was used as further evidence for a bulbospinal motor generator. Combining our findings with current basic knowledge of the acoustic startle response allows one to speculate as to the neuronal localization of the hyperexcitability. Davis and associates 187 mapped the neural substrates of the acoustic startle circuit in rats. In experiments using brain lesions or stimulation, they showed that the shortest latency components of the startle reflex traverse four brainstem nuclei: the ventral cochlear nucleus, the dorsal nucleus of the lateral lemniscus, the nucleus reticularis pontis caudalis, and the cranial and somatic alpha motor neurons. Hyperexcitability at any point in this reflex arc could explain our findings, but the reticular formation seems most probable. The abnormality is unlikely to be located in acoustic sensory neurons, because multimodal sensory input elicits pathological jerks, and brainstem auditory
evoked responses are normal. In addition, habituation, which develops on the sensory side of a reflex arc [7}, could be demonstrated even in the most severely affected patient, albeit at a much less effective level. The patterned motor response in widespread muscles and the absence of marked exaggerated monosynaptic reflexes make alpha motor neuronal hyperexcitability unlikely. It therefore seems likely that the pontomedullary reticular formation is one locus of hyperexcitability in hyperekplexia. By the measure of efferent spinal cord conduction used in this study, the reticular neurons involved in the acoustic startle response in hyperekplexia utilize axons with conduction velocities of 34 to 133 m/sec and with maximal conduction velocities of 76 to 133 m/sec. It is acknowledged that this measure is at best an estimate, because there is a question of whether the same reticular neurons innervate both cervical and lumbar paraspinal muscles. However, on the basis of experimental data, it seems likely that branching reticulospinal axons would be found in the paraspinal regions [1O}. Further, this method is analogous to the one used by Shimamura and coworkers [l If in calculating reticulospinal conduction in animal preparations. Our values do correspond to those reported for single-unit antidromic and orthodromic stimulation of the pontomedullary reticular formation in the cat, which range from 20 to 150 m/sec, with most axons functioning near maximal values of 100 to 130 m/sec [12--141. They also correspond to the conduction velocity of 100 m/sec reported for neurons involved in the acoustic startle response of the cat [l5}. The estimated efferent spinal cord conduction velocities therefore serve as further evidence of involvement of the acoustic startle circuit in hyperekplexia. While there is great similarity in the EMG patterns of hyperekplectic and normal startle responses, there are also quantitative differences, which may explain the pathophysiology in reticular neurons. Suhren and colleagues [l} noted shortened EMG onset latencies of responses to pistol shots in the orbicularis oculi and trapezius muscles of hyperekplectic patients. Our study showed a similar tendency in both cranial and somatic muscles. In the most severely affected patient, we found progressive shortening of EMG onset latencies in all muscles with increasing stimulus intensities. Recruitment of larger alpha motor neurons with faster conducting peripheral axons can not entirely explain this phenomenon, because differences in onset latencies as large as 50 msec occur in muscles with short peripheral segments, such as cranial and paraspinal muscles. Our finding of increasing efferent spinal cord conduction velocities to gradually increasing stimulus intensities supports the hypothesis that central mechanisms are responsible. One possible explanation for this phenomenon is that at higher stimulus intensities, Matsumoto et ak Hereditary Hyperekplexia 47
there is an orderly recruitment of larger reticular neurons with more direct and faster reticulospinal connections. Another possible explanation is that the reticulospinal output is composed of a series of excitatory discharges. At low stimulus intensities, the response results from temporal summation. At higher intensities, the initial excitatory discharges are larger, giving rise to greater early spatial summation and the resultant shorter onset latencies. In the patients, we noted a graded increase in the response to increasing stimulus intensities, as occurs in normal startle, but the response was greater at any given level, and the response threshold was approximately 25 dB lower than that in the control subjects. Hyperekplexia seems to represent heightened gain of the normal startle reflex. The behavior of the acoustic startle response in Patient 3 provides insight into the neural basis for this response in humans. The orbicularis oculi has the lowest threshold and recruits rapidly, reflecting the importance of reflex protective eye closure. The sternocleidomastoid has the second lowest threshold. The excessively long latency of the response from the abductor pollis brevis may represent a high threshold of neurons involved in the activation of this muscle. However, even at near-maximal recruitment, the response from the abductor pollicis brevis is 20 msec longer than that from the triceps or biceps. An additional factor may be that smaller, slower-conducting reticulospinal axons innervate abductor pollicis brevis motor neurons in a manner consistent with the known axial predominance of the reticulospinal tract. The nature of the motor response is thus determined by the differential thresholds and shapes of the recruitment curves. The reflex myoclonic jerk in response to nose tapping is a characteristic abnormality in hyperekplexia 116, 17). Andermann and coauthors 1181 reported associated EMG bursts in the limbs at latencies shorter than those elicited by sound. In our hyperekplectic patients, short-duration EMG bursts with extremely short onset latencies were noted in cranial, spinal, and limb muscles. The abnormal response is similar in latency to the R1 component of the blink reflex, which is mediated by an oligosynaptic pathway comprising the trigeminal neuron, a reticular neuron, and the facial motor neuron C19). The more variable R2 late response is a polysynaptic pathway involving a greater number of intervening pontomedullary reticular neurons. By arguments similar to those presented earlier, we believe that the locus of excitability in this manifestation of hyperekplexia lies within the reticular formation, but it seems that a different pathway is involved. The EMG bursts in response to nose tapping are much less variable and of shorter duration than those involved in the acoustic startle response. In addition, they are less prone to habituation, and the order of activation of the muscles in relation to the orbicularis 48 Annals of Neurology Vol 32 No 1 July 1992
oculi is different from that evoked by noise. We hypothesize that patients with hyperekplexia exhibit generdzed R1-like motor reflexes to this type of trigeminal stimulation. Scheibel and associates 120) identified bulbar reticular neurons that were selectively driven by nose pressure in the cat. Such neurons may organize a primitive oligosynaptic withdrawal reflex, which is unmasked in hyperekplexia. Brown and coworkers 177 also studied responses to taps in the “mantle area.” They suggested that the early response in the orbicularis oculi was normal and that the later activity characterized the startle reflex. Looked at in this way, the sternocleidomastoid muscle was the earliest activated, and the full pattern of muscle activation was sufficiently similar to the acoustic startle reflex that the two reflexes were considered the same. Further work will be necessary to resolve this difference in interpretation. Electrical stimuli elicited generalized motor responses in 2 patients, and 1 patient demonstrated responses to both median and peroneal nerve stimulation. The pattern of these responses was different from those elicited by acoustic or trigeminal stimulation. In the cranial musculature, the EMG activation appeared similar to that evoked by acoustic stimuli, which suggests that somatosensory stimuli from the limbs project to the same polysynaptic pontomedullary reticular pathways as acoustic stimuli. In the leg, however, the pattern was unique, with EMG activation in the stimulated leg occurring earlier than would be expected in the acoustic startle response. The pattern of activation with peroneal nerve stimulation was identical to that observed with high-frequency plantar stimulation delivered in a manner described for stimulation of the flexor reflex 121). Although we have no comparative normative data, flexor responses are reported as being uncommon to single shocks and are of low amplitude when present [2 13. This raises the possibility that spinal neurons within the flexor reflex chain are also hyperexcitable in hyperekplexia. Our median values of 69 m/sec for the efferent spinal cord conduction velocity to acous*ic stimuli and 107 m/sec for afferent spinal cord conduction velocity to somatosensory stimuli differ from those for the spinobulbospinal reflex reported in dogs and monkeys [l 11, in which the efferent velocity is 30 m/sec and the afferent velocity is 60 m/sec. However, the relative conduction velocities are preserved, with afferent conduction being approximately twice as fast as efferent conduction 111). Karpukhina and colleagues 122) found that nocioceptive stimuli activated medullary reticular neurons with axonal conduction velocities of approximately 3 3 m/sec. Non-nocioceptive stimuli, on the other hand, more selectively activated reticular neurons within the nucleus reticularis pontis caudalis with faster axonal conduction velocities of approximately 84 m/sec. Our values may reflect hyperexcit-
ability in this latter circuit rather than the classic spinobulbospinal reflex. Photic stimulation was ineffective in producing generahzed startle responses in the patients despite their complaints of jerks to sudden nearby movements. It is possible that the noise accompanying such movements, rather than the visual stimulus itself, triggers the startle response. The most prominent physiological abnormality in hereditary hyperekplexia is a lowered threshold in pontomedullary reticular neurons, resulting in an increased gain of a number of vestigial reflexes, all of which are present to a lesser degree in normal subjects. Hereditary hyperekplexia thus represents a specific reticular reflex disorder. Current evidence divides the brainstem reticular formation into discrete nuclei with specific input-output relationships I231. The reticular formation acts to regulate the gain between sensory input and motor, autonomic, and ascending output I241. A patient with reticular reflex myoclonus secondary to anoxia, described by Hallett and coauthors 1251, had brief, short-latency EMG bursts occurring predominantly with limb stimulation, as well as EEG spikes appearing with variable latencies following the myoclonus. It seems clear that the gain of specific reticular reflexes was increased in this patient, but in a different manner than in those with hereditary hyperekplexia, in which burst durations are longer and trigeminal and acoustic stimulation is most effective. It is anticipated that future studies will identify a variety of reticular reflex disorders. Our data suggest that hereditary hyperekplexia may involve spinal as well as brainstem hyperexcitability. Because the reticular formation is a rostral extension of the spinal gray matter, such an overlap would not be unexpected. Spinal hyperexcitability could explain the spasticity, hyperreflexia, and muscle stiffness seen in some patients with hyperekplexia, as well as the features of hyperekplexia seen in some patients with stiff-man syndrome E261. The widespread nature of hyperexcitability in hyperekplexia is extended further by the reports of abnormal EEG activity and enlarged somatosensory evoked potentials 12, 51. Because our patients did not exhibit cortical abnormalities, it appears that this is a variable manifestation of the disease. A genetic error in a common neurochemical system (such as the gamma-aminobutyric acid system) could explain the widespread physiological abnormalities. Because hyperekplexia represents an exaggeration of normal withdrawal reflexes, it is unlikely that any single electrophysiological test could clearly separate mildly affected patients from unaffected subjects. The finding in an adult of short-latency EMG bursts in the limb, lower paraspinal, and sternocleidomastoid muscles to nose tapping is sufficiently unusual to be supportive of the diagnosis. The soecificity for hyperek-
plexia is not established, however. The issue of these trigeminomotor reflexes in normal newborns or children has not been addressed, and the value of this test in pediatric hyperekplexia is undefined. The topic may warrant further investigation given the known association of hyperekplexia with the sudden infant death syndrome 127).
We thank B. J. Hessie for editorial assistance.
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