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Relative preservation of finger flexion in amyotrophic lateral sclerosis

Published:December 21, 2015DOI:https://doi.org/10.1016/j.jns.2015.12.028

      Abstract

      A characteristic pattern of intrinsic hand muscle involvement—known as the split hand sign—is typical of ALS; differential involvement of forearm muscles has not been examined systematically.
      After observing that finger-flexion was often preserved in ALS, despite severe weakness of finger-extension, we assessed the relative involvement of these two muscle groups in a cohort of patients with ALS.
      We found finger-flexion to be relatively preserved, when compared with finger-extension, in patients with ALS. In many cases finger-flexion is only minimally affected, even when finger-extension is totally paralyzed.
      The reasons for this predilection are unclear, but may be similar to those underlying the split-hand sign. Nevertheless, the discrepancy may provide another useful clinical clue in patients presenting with distal upper-limb weakness.

      Keywords

      1. Introduction

      Neuromuscular diseases may be recognized by a characteristic pattern of muscle weakness; examples include: distal upper-limb weakness in multifocal motor neuropathy [
      • Pestronk A.
      Multifocal motor neuropathy: diagnosis and treatment.
      ], oculobulbar involvement in myasthenia gravis [
      • Engel A.
      Myasthenia Gravis and Myasthenic Disorders.
      ], finger flexor and quadriceps predilection in sporadic inclusion body myositis [
      • Amato A.A.
      • Gronseth G.S.
      • Jackson C.E.
      • Wolfe G.I.
      • Katz J.S.
      • Bryan W.W.
      • et al.
      Inclusion body myositis: clinical and pathological boundaries.
      ] and sparing of the quadriceps in hereditary inclusion body myopathy [
      • Argov Z.
      • Yarom R.
      “Rimmed vacuole myopathy” sparing the quadriceps. A unique disorder in Iranian Jews.
      ].
      Advanced amyotrophic lateral sclerosis (ALS) is characterized by sparing of extra-ocular and sphincter muscles—no other voluntary muscle group is spared consistently in late disease [
      • Traynor B.J.
      • Codd M.B.
      • Corr B.
      • Forde C.
      • Frost E.
      • Hardiman O.M.
      Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study.
      ,
      • Brooks B.R.
      • Lewis D.
      • Rawling J.
      • Sanjak M.
      • Belden D.
      • Hakim H.
      • et al.
      The natural history of amyotrophic lateral sclerosis.
      ]. The split hand sign describes preferential involvement of lateral intrinsic hand muscles, with relative sparing of medially placed muscles [
      • Wilbourn A.J.
      The “split hand syndrome”.
      ,
      • Menon P.
      • Bae J.S.
      • Mioshi E.
      • Kiernan M.C.
      • Vucic S.
      Split-hand plus sign in ALS: differential involvement of the flexor pollicis longus and intrinsic hand muscles.
      ,
      • Menon P.
      • Kiernan M.C.
      • Yiannikas C.
      • Stroud J.
      • Vucic S.
      Split-hand index for the diagnosis of amyotrophic lateral sclerosis.
      ,
      • Kim D.G.
      • Hong Y.H.
      • Shin J.Y.
      • Park K.H.
      • Sohn S.Y.
      • Lee K.W.
      • et al.
      Split hand phenomenon in amyotrophic lateral sclerosis: a motor unit number index study.
      ,
      • Kuwabara S.
      • Sonoo M.
      • Komori T.
      • Shimizu T.
      • Hirashima F.
      • Inaba A.
      • et al.
      Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis: frequency, extent, and specificity.
      ,
      • Kuwabara S.
      • Mizobuchi K.
      • Ogawara K.
      • Hattori T.
      Dissociated small hand muscle involvement in amyotrophic lateral sclerosis detected by motor unit number estimates.
      ]. We observed that in the early stages of ALS, finger-flexion (FF) was often unaffected in patients with pronounced weakness of finger-extension (FE) (video clip). This led us to assess the relative involvement of these two muscle groups on a systematic basis.

      2. Methods

      Muscle strength of patients visiting our ALS clinic between 2009 and 2013 was assessed using the MRC scale for muscle strength (by MG). MRC grade 4 was subdivided into 4+, 4 and 4−. We collected data from patients with suspected, possible, probable or definite ALS, but limited analysis to patients eventually diagnosed with probable or definite ALS, according to revised El Escorial Criteria [
      • Brooks B.R.
      • Miller R.G.
      • Swash M.
      • Munsat T.L.
      World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.
      ]. Data analysis was retrospective, using data in our ALS database.
      For each of the muscle groups (FF and FE) muscle force was graded separately in each upper-limb. We then determined the first occasion on which moderate or severe weakness was present (MRC < 4) in each tested muscle group. Muscle strength at that time-point was compared to the strength of the ipsilateral antagonist muscle group at the same time-point, yielding a data-pair. The upper-limbs of each patient were analyzed separately, thus each patient could provide between 0 and 4 data-pairs for analysis. Our institutional review board approved the study.

      3. Results

      A total of 346 patients fulfilling ALS diagnostic criteria provided data for our analysis; this corresponds to a total of 1384 potential data-pairs (692 for each muscle group). Data from these patients yielded 312 data-pairs due to FE-MRC falling below 4, whereas 157 data-pairs were captured due to FF-MRC falling below 4. In all cases in which weakness FF-MRC was <4, ipsilateral FE was either as weak or weaker (Fig. 1, upper section). Conversely, whenever FE-MRC was <4, FF was either as strong or stronger (Fig. 1, lower section). These results were highly significant (McNemar's test, P<0.001). In 62.8% (196/312) of cases of MRC-FE ≤ (−) 4, the strength of ipsilateral FF was preserved or only mildly affected (≥4). This pattern was preserved, even when upper-limbs with increased tone were excluded from analysis (data not shown).
      Figure thumbnail gr1
      Fig. 1Relative muscle force of finger flexors (FF) and extensors (FE) in ALS. The upper part of the figure presents the relative weakness of FE as FF weakness progresses. Strength was measured based on the MRC scale. The lower part of the figure presents a 'mirror image' - the relatively preserved strength of FF, compared to FE weakness.

      4. Discussion

      This data demonstrates that FF is relatively preserved, when compared with FE, in patients who ultimately receive a diagnosis of ALS. Moreover, in many cases FF was only mildly affected, even when FE was paralyzed; this implies that this pattern of predilection is preserved until complete paralysis of the fingers occurs with disease progression. The difference between these muscle groups was present even when analysis was limited to upper-limbs without increased tone, arguing against the phenomenon being a manifestation of spasticity. The predilection may be due to differences in functional reserves—as the FF muscle group is physiologically more powerful than the FE group—or to different susceptibilities of the neuronal populations related to these two muscle groups.
      The pathophysiological basis of the discrepancy between FF and FE may be similar to that underling the split hand sign. The APB and FDI muscles are more generously represented in the motor cortex than other intrinsic hand muscles, suggesting a cortical origin for the split hand sign [
      • Menon P.
      • Kiernan M.C.
      • Yiannikas C.
      • Stroud J.
      • Vucic S.
      Split-hand index for the diagnosis of amyotrophic lateral sclerosis.
      ]. More importantly, cortical hyperexcitability—a hallmark of ALS—is observed in all intrinsic hand muscles of patients, although most prominently in the APB and FDI muscles [
      • Menon P.
      • Kiernan M.C.
      • Vucic S.
      Cortical dysfunction underlies the development of the split-hand in amyotrophic lateral sclerosis.
      ,
      • Bae J.S.
      • Menon P.
      • Mioshi E.
      • Kiernan M.C.
      • Vucic S.
      Cortical hyperexcitability and the split-hand plus phenomenon: pathophysiological insights in ALS.
      ]. Furthermore, cortical excitability in healthy controls also follows a split hand pattern [
      • Menon P.
      • Kiernan M.C.
      • Vucic S.
      Cortical excitability differences in hand muscles follow a split-hand pattern in healthy controls.
      ]; thus differential baseline cortical excitability is likely to be underlying the development of the split hand phenomenon. As such, it would be interesting to examine differences in cortical excitability parameters between muscles involved in FF compared to those involved in FE, in patients with ALS and healthy controls. We hypothesize that the correlates of cortical hyperexcitability will be most prominent when measured in FE muscles, compared to FF muscles, thus extending the pattern observed in the intrinsic hand muscles, to the forearm.
      Finger flexion tasks are often chosen in fMRI studies on the basis of simplicity [
      • Konrad C.
      • Jansen A.
      • Henningsen H.
      • Sommer J.
      • Turski P.A.
      • Brooks B.R.
      • et al.
      Subcortical reorganization in amyotrophic lateral sclerosis.
      ,
      • Konrad C.
      • Henningsen H.
      • Bremer J.
      • Mock B.
      • Deppe M.
      • Buchinger C.
      • et al.
      Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study.
      ]. These studies demonstrate increased activation of areas usually involved in planning and initiation of movement [
      • Konrad C.
      • Henningsen H.
      • Bremer J.
      • Mock B.
      • Deppe M.
      • Buchinger C.
      • et al.
      Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study.
      ] as well as subcortical structures [
      • Konrad C.
      • Jansen A.
      • Henningsen H.
      • Sommer J.
      • Turski P.A.
      • Brooks B.R.
      • et al.
      Subcortical reorganization in amyotrophic lateral sclerosis.
      ], in patients with ALS. Increased activation observed during FF tasks in ALS seems less likely to be due to new synaptic connections and is probably related to enhanced recruitment of existing resources—a phenomenon which may be related to the increased effort needed to perform the tasks [
      • Schoenfeld M.A.
      • Tempelmann C.
      • Gaul C.
      • Kuhnel G.R.
      • Duzel E.
      • Hopf J.M.
      • et al.
      Functional motor compensation in amyotrophic lateral sclerosis.
      ]. To our knowledge, no study has investigated how fMRI activation patterns change in ALS using separate FF and FE paradigms. Conclusions derived from paradigms focusing on a muscle group that is selectively preserved in ALS—namely FF—may not be able to be extrapolated to other muscle groups. For example, the increased cortical recruitment in FF paradigms could be related, in part, to the effort needed to modulate FF strength in the presence of disproportionally weak antagonist muscles.
      Since completing this study, we have found this pattern to be a useful clinical clue, in patients presenting with undiagnosed progressive upper-limb weakness. Unlike preservation of eye movements, which is observed even in very advanced disease, the discrepancy between FF and FE can only be appreciated in earlier stages, before limb paralysis is complete; in this respect its clinical utility is similar to the split hand sign.
      The following is the supplementary data related to this article.

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