LLR in Parkinsonian Syndromes (n = 11 Studies)

One of the earliest diseases where LLR was studied was Parkinson’s disease (PD). Of the 11 studies included on parkinsonian syndromes, the majority of the studies were on PD. The foundation was laid by Tatton and Lee in 1975, who for the first time analyzed the reflex responses to wrist flexion-extension movements in rigidity predominant parkinsonian patients.^{Reference Tatton and Lee18} They demonstrated a significant increase in response at the M2-M3 interval which was statistically significant compared to the controls. The minimally increased M1 response in the parkinsonian group was consistent with the clinical correlate of normal tendon reflex in this condition. The study by Hunter et al. on reflex pathways in parkinsonian patients revealed exaggerated LLR at a mean latency of 61.3 ± 5.1 ms suggestive of enhanced LLR II. Lack of LLR on stimulation of cutaneous afferents near fibular nerve, suggested the origin to be the fast-conducting non-cutaneous group I afferents.^{Reference Hunter, Ashby and Lang23} Rothwell et al. hypothesized that the parkinsonian rigidity stems from the quantitative alterations in the long loop pathways.^{Reference Rothwell, Obeso, Traub and Marsden24} A similar observation of enhanced LLR was also found by other researchers (Table 1).^{Reference Mortimer and Webster25,Reference Berardelli, Sabra and Hallett26,Reference Cody, Macdermott, Matthews and Richardson27}

Table 1: Studies of LLR in Parkinsonian disorders

FPL: Flexor pollicis longus; LLR: Long latency reflex; MLR: medium latency reflex; PD: Parkinson’s disease; PPND: Pallido-ponto-nigral degeneration; SLR: short latency reflex; TB: Triceps brachii.

Role of MLR, LLR in “Off state” and Other Controversies. Studies of stretch reflexes in lower limbs of parkinsonian patients, demonstrated exaggeration of MLR, instead of LLR.^{Reference Scholz, Diener, Noth, Friedemann, Dichgans and Bacher28,Reference Bloem, Beckley, van Dijk, Zwinderman and Roos29} The study by Bloem et al. stands out from the previous studies concerning the methodology as they tested reflexes among PD patients in 12 hours “off” state. Their results did not attribute any significant early diagnostic value to these parameters, as altered reflex responses (MLR) was noted only among advanced long-standing PD patients.^{Reference Bloem, Beckley, van Dijk, Zwinderman and Roos29} The study effectively sheds light on the supraspinal dopaminergic control of LLR, which is the pathomechanism behind low LLR response in the off state. Besides, it also showed the poor diagnostic sensitivity of LLR in detecting early PD. In another study, SLR was found to be absent to both mechanical and electrical stimuli and LLR was detected to be of normal parameters.^{Reference Noth, Schürmann, Podoll and Schwarz30} While the former was hypothesized to be a result of altered fusimotor drive in PD patients, the latter was postulated to be due to the dependence of these reflexes on the degree of muscle length perturbations applied.^{Reference Noth, Schürmann, Podoll and Schwarz30} The experimental study by Fuhr et al. revealed a less pronounced first inhibitory component (I1) of the cutaneous reflex (CR) attributed to the loss of spinal inhibition in PD patients.^{Reference Fuhr, Zeffiro and Hallett31} In a single study on Ponto-pallido-nigral degeneration (PPND), Wszolek et al. showed the absence of LLR in a family of nine patients associated with chromosome 17q21-24, suggesting lack of cortical hyperexcitability.^{Reference Wszolek, Lagerlund, Steg and McManis32}

LLR in Myoclonus (n = 13 Studies)

Myoclonus has been subjected to numerous levels of classifications based on clinical aspects, anatomical location, electrophysiological patterns, including transcranial magnetic stimulation (TMS), somatosensory evoked potentials (SEP), and LLR.^{Reference Shibasaki33,Reference Kojovic, Cordivari and Bhatia34,Reference Tassinari, Rubboli and Shibasaki35} Enhanced LLR I is most commonly observed followed by LLR III and rarely LLR II.^{Reference Cruccu and Deuschl36} One of the earliest studies on detailed electrophysiology in a patient of focal reflex myoclonus was carried out by Sutton and Mayer, where they demonstrated exaggerated LLR at a mean latency of 51 ms suggestive of LLR II, generated by the sensorimotor cortex, also called C-reflex (cortical reflex).^{Reference Sutton and Mayer37} Based on etiology, myoclonus may be physiological, essential with or without dystonia, epileptic, and symptomatic or secondary.^{Reference Kojovic, Cordivari and Bhatia34} Of the 13 included studies on myoclonus, 5 were on symptomatic myoclonus, where myoclonus was a part of another disease, 3 on essential myoclonus comprising the hereditary etiologies, and 5 were on progressive myoclonic epilepsy syndromes (Table 2).

Table 2: Studies of LLR in myoclonus

BAFME: Benign adult familial myoclonic epilepsy; CBD: cortico-basal degeneration; LBD: Lafora body disease; LLR: long latency reflex; MD: myoclonus-dystonia; MLR: medium latency reflex; SEP: somatosensory evoked potential; SLR: short latency reflex; ULD: Unverricht-Lundborg disease.

LLR in PME Syndromes

Unverricht–Lundborg Disease (ULD) and Lafora Body Disease (LBD ): Canafoglia et al. demonstrated consistently enlarged LLR in 8 ULD patients that correlated with enlarged P25 and N33 components of SEP.^{Reference Canafoglia, Ciano and Panzica48} The enlarged LLR in ULD is a single wave that is a mixture of LLR I and LLR II. LLR enlargement was less consistent in patients with LBD. However, they had enlarged mid-latency N60 component of SEP, attributable to the sustained and complex cortical circuitry. Facilitated LLR was also reported in a series of 25 patients with ULD.^{Reference Visani, Canafoglia and Sebastiano49} LLR subtype couldn't be delineated in these cases due to lack of data.^{Reference Visani, Canafoglia and Sebastiano49}

Sialidosis: Canafoglia et al. showed multiphasic complex waveforms (2–3 components) in 3 patients with sialidosis compared to 10 ULD patients suggesting the presence of reverberating loops involving the motor cortex and subcortical-cerebellar connections.^{Reference Canafoglia, Franceschetti and Uziel50} The enhanced LLR corresponds to LLR II.

Benign Adult Familial Myoclonic Epilepsy (BAFME): Demura et al. evaluated a single family of BAFME, of which three patients had SAMD 12 gene mutation, one of which was found to have C-reflex (correlate of LLR in myoclonus) at 77 ms latency of onset (LLR III).^{Reference Demura, Demura, Ota, Kondo and Kinoshita51} It corroborated with giant flash visual evoked potential (VEP). The longer latency of the C-reflex obtained in these patients could be attributed to the technique used in this study. Contrary to the usual electrical test of LLR, the C-reflex was obtained using F-wave study from abductor hallucis muscle. Since the stimulation intensity used in F-wave tests is higher than that of electrical LLR test, the response might be induced from all types of afferent nerves, but not Ia/II only. Enhanced LLR I, enlarged SEP and positive spikes preceding myoclonus on jerk locked back averaging (JLBA) has been described in three patients with BAFME.^{Reference Manabe, Narai and Warita52}

LLR in Huntington’s Disease (n = 10 Studies)

Noth et al. did not observe LLR in majority of the patients with HD which corroborated with reduced early cortical components of SEP amplitude.^{Reference Noth, Friedemann, Podoll and Lange53} Other studies by Thompson et al., and Noth et al. on 17 and 50 HD patients demonstrated similar results.^{Reference Thompson, Berardelli and Rothwell54,Reference Noth, Podoll and Friedemann55} Eisen et al. demonstrated absent R2 (equivalent to LLR) in majority of HD patients and half of at-risk subjects.^{Reference Eisen, Bohlega and Hayden56} In 1989, a study on 23 patients of HD by Deuschl et al., provided valuable insights as it concluded loss of LLR as fairly specific in HD. They showed lack of utility of LLR in detecting carriers of HD.^{Reference Deuschl, Lucking and Schenck57} Lefaucheur et al. studied 36 patients with adult-onset HD using various neurophysiologic measures. While the role of SEP was quite apparent as a sensitive marker of disease, LLR did not correlate with disease stage or duration.^{Reference Lefaucheur, Bachoud-Levi and Bourdet13} Two years follow up study of 20 patients with HD, LLR correlated with an increase in unified Huntington disease rating scale (UHDRS) motor score.^{Reference Lefaucheur, Menard-Lefaucheur and Maison58} Sebastiano et al. described three patients with HD, who had enhanced LLRs suggestive of a reverberant circuit involving motor cortex.^{Reference Rossi Sebastiano, Soliveri and Panzica59} Delayed LLR latency and prolonged duration were described in 27 HD patients by Huttunen et al. (Table 3).^{Reference Huttunen and Homberg60}

Table 3: Studies of LLR in Huntington’s disease

HD: Huntington’s disease; HR: H-reflex; LLR: Long latency reflex; MLR: medium latency reflex; SLR: short latency reflex.

Applications in Multiple Sclerosis (MS) (n = 6 Studies)

Deuschl et al. studied 47 patients with probable and definite MS. Pathological LLR was found in 79 and 61% of confirmed and probable MS which was statistically significant when compared to SSEP.^{Reference Dueschl, Strahl, Schenck and Lücking72} In a study of 23 patients with acute phase MS, there was prolongation of LLR II latency, suggestive of impairment along the LLR pathway.^{Reference Bonfiglio, Rossi and Sartucci73} Abnormalities either in the afferent or efferent pathway can lead to altered LLR II latency, unlike SEP which is dependent only on the afferent system, that explains more frequent abnormality of LLR compared to SEP among MS patients. Many other studies also highlighted the intracortical delay as the principal factor behind the increased LLR latency among MS patients, the sensitivity of which exceeds that of SEP (Table 4).^{Reference Iovichich74,Reference Michels and Wessel75,Reference Matsumoto and Kaneshige76,Reference Toydemİr, Gökyİğİt, Seleker and Çelebİ77}

Table 4: Studies of LLR in Multiple sclerosis

LLR: Long latency reflex; MLR: medium latency reflex; MS: Multiple sclerosis; SEP: somatosensory evoked potential; SLR: short latency reflex.

Applications in Miscellaneous Neurological and Non-neurological Conditions

LLR in Cerebellar Disorders (n = 2 Studies): Friedman et al. evaluated stretch induced LLR response in patients with cerebellar disorders. They revealed the presence of enlarged M2/M3 complex (LLR II/III) in disorders of cerebellar hemisphere, lower vermis and anterior lobe atrophy. On the contrary, diffuse cerebellar lesions didn't reveal any conclusive findings. In the Friedreich’s ataxia subgroup, patients had markedly delayed or absence of M2/M3 complex. Authors have mentioned the limitation of distinguishing M2 and M3 response separately in view of overlapping latencies. Abnormalities of M3 response points towards the role of trans-cerebellar loop in modulation of M3 component of LLR.^{Reference Friedemann, Noth, Diener and Bacher78} In a study of 41 subjects with cerebellar disease by Diener et al., the SLR and MLR elicited by stretching triceps surae and LLR in the antagonist muscle (tibialis anterior) were found to be normal in patients with lesions restricted to cerebellar hemispheres or vestibulocerebellum; suggesting that the exact timing of these reflexes is independent of the cerebellum. Three patients with Friedreich’s ataxia had delayed MLR probably attributable to the suprasegmental pathway, and markedly delayed M3 response.^{Reference Diener, Dichgans, Bacher and Guschlbauer79}

LLR in Cortical Dementia (n = 1 Study): In a pilot study of patients with fronto-temporal dementia (FTD), LLR II response was not observed in comparison to patients with Alzheimer’s disease (AD), who had normal LLR II response.^{Reference Chandra, Isaac, Mane, Bharath and Nagaraju80}

LLR in Brain Tumor (n = 1 Study): Stetkarova et al. reported a case series of 3 patients with brain tumor adjoining central sulcus. All had enhanced SEP and only one had exaggerated LLR. The latencies have not been mentioned in the article. The results are attributed to the increased cortical hyperexcitability or suppression of cortical inhibitory activity.^{Reference Stetkarova, Stejskal and Kofler81}

LLR in Rasmussen Encephalitis (n = 1 Study): Gündüz et al. studied LLR in three patients with Rasmussen encephalitis, and found the presence of enhanced LLR in all cases. One of the patients had C- reflex at a latency of 55 ms, suggestive of LLR II response. For the rest of patients, the latencies were not mentioned in the paper. The findings were attributed to the involvement of cortical pathways in stimulus sensitive positive and negative myoclonus.^{Reference Gündüz, Kiziltan, Coşkun, Delil, Yeni and Özkara82}

LLR in Adrenomyeloneuropathy (n = 1 Study): Liao et al. measured LLR and CRT in 2 patients with normal MRI and compared with 10 controls. They demonstrated delayed LLR with a latency that corresponds to LLR II.^{Reference Liao, Chen, Lin, Chen, Kao and Wu83}

LLR in Myotonic Dystrophy Type 1 (DM1) (n = 1 Study): In a study of 24 patients with DM1, abnormalities in the muscle twitch properties such as reduced H-reflex depression with less robust LLR response was observed.^{Reference Shields, Petrie and Ba84}

LLR in Stroke (n = 3 Studies) and Neurorehabilitation (n = 1 Study): Results of LLR assessment among long term stroke-survivors were contradictory.^{Reference Faig and Busse85,Reference Groenewegen, de Groot, Schouten, Maier, Arendzen and Meskers86,Reference Trumbower, Finley, Shemmell, Honeycutt and Perreault87} A more recent study by Bank C et al. showed that stroke survivors with intact LLR, have a better clinical recovery with respect to walking speed and power of ankle flexors compared to healthy controls. Patients who were LLR negative had dysfunctional modulation of stretch responses.^{Reference Banks, Little, Walker and Patten88} This highlights the potential role of LLR in the assessment of post-stroke recovery.

LLR in Idiopathic Scoliosis (n = 1 Study): Maguire et al. studied segmental reflex regulation in 37 patients with idiopathic scoliosis and 8 patients with secondary scoliosis, and demonstrated the presence of LLR in the idiopathic and their absence in the secondary group indicating the role of aberrant reflex pathways in the development of scoliosis.^{Reference Maguire, Madigan, Wallace, Draper and Leppanen14}

LLR in Chronic Low Back Pain (n = 1 study): Shenoy et al. studied surface electromyograph of erector spinae and rectus abdominis muscles in athletes with chronic non-specific low backache (n = 25) and asymptomatic athletes (n = 24). They showed that symptomatic athletes had lower amplitude and delayed onset of LLR to unexpected perturbations, which is attributable to the task-modulated training of LLR which gets impaired in symptomatic athletes.^{Reference Shenoy, Balachander and Sandhu15}

LLR and Theophyline (n = 1 Study): Bartel et al. studied the neurophysiological impact of theophylline on healthy volunteers. LLR showed no definite alterations from normal and no change following B6 supplementation. F wave latencies reduced and the percentage increased, highlighting the stimulatory effect of theophylline on neuraxis.^{Reference Bartel, Lotz, Delpori, Ubbink and Becker89}