Classification of Motor Neurone Diseases

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The table below gives an overview of the ways in which various forms of MND are traditionally classified. In the UK, "MND" is both a blanket term referring to the whole spectrum of diseases which differentially affect the upper and lower motor neurones, and also refers specifically the most common form, ALS. In the United States, the terms ALS or Lou Gehrig's Disease are used.

Combined UMN and LMN involvement • Amyotrophic lateral sclerosis (ALS)
Pure LMN involvement • Progressive Muscular Atrophy (PMA) • Proximal hereditary motor neuropathy• Hereditary bulbar palsy • Hexosaminidase deficiency • Multifocal motor neuropathies• Post polio syndrome • Post irradiation syndrome• Monomelic, focal or segmental spinal muscular atrophy (SMA)
Pure UMN involvement • Primary lateral sclerosis (PLS)• Hereditary spastic paraplegia (HSP)• Neurolathyrism• Konzo
Mixed Motor and Sensory involvement • ALS with fronto-temporal dementia (ALS-FTD)• Charcot Marie Tooth Disease (CMT)• Distal hereditary motor neuropathy

Increasingly, it is recognised that there is not a clear distinction between PMA, ALS, PLS, and ALS-FTD. As has been hypothesized in the fields of neuropsychology and neuroimaging , a number of authors in the neuropathology literature have suggested that MND is best considered as a multisystem disorder with a number of phenotypes expressing differential involvement of motor and CNS systems (Iwanaga et al. 1997 Maekawa et al. 2004 Wilson et al. 1996 Yoshida 2004 Ince et al. 2003 This hypothesis is supported by evidence that neuropathologically, MND cannot be subdivided into pure and distinct categories as identified by clinical signs and symptoms. Table 1 shows an overview of pathological change in the known subgroups of MND. For example, a loss of Betz cells in the motor cortex and myelin pallor was found in the corticospinal tract (both UMN signs) in two patients with long-duration PMA, thought previously to exclusively affect the LMNs (Iwanaga et al. 1997 In a review of cases including 12 PMA patients, 75% were found to have neuropathological or clinical evidence of UMN degeneration (Ince et al. 2003 Similarly, a number of reviews have pointed to LMN changes in PLS invalidating the notion of a distinct nosological entity (Rowland 1999 Le Forestier et al. 2001a Swash et al. 1999

Specifically, the evidence shows that in up to 50% of cases the PLS syndrome progresses to ‘classical’ ALS and that on autopsy a small number of cases show LMN signs such as loss of pallor and demyelination of the corticospinal tract. Electrophysiology has also revealed that LMNs may show transient or chronic denervation in PLS patients, further eroding the concept of PLS as separate from ALS. Finally, the heterogeneity of extra-motor neuronal loss and cognitive change in ALS and ALS-FTD pathology suggests an overlap between these two conditions (Bigio et al. 2003 Neary et al. 2000 The implication for these findings is that whilst it is clinically reasonable and pragmatic to subdivide manifestations of disease on the basis of evident signs and symptoms, these do not necessarily reflect the underlying pathology.

Table 1: Proposed spectrum of neuropathological involvement in MND (adapted from Ince et al. 1998
Syndrome LMN UMN Hippo-Campus Frontal Cortex Other CNS regions involved
PMA ++ +/- - - ?UMN
ALS + + +/- +/- ?SN, spinsocerebellar, sensory, autonomic systems, thalamus
FALS + + +/- +/- ?As ALS ?More cortical involvement
PLS +/- ++ + + ?LMN ?Caudate & putamen
ALSi + + + + ?Temporal, occipital & entorhinal cortices, caudate, & putamen
ALS-FTD ++ +/- + ++ ?As ALS, also Temporal cortex, substantia nigra, neocortical spongiform changes
MND-IBD - - ++ ++ ?Temporal cortex

Abbreviations
+ Pathological Change (i.e. inclusion bodies, neuronal loss, astrocytosis, UIBs, SCIs

++ Predominant Pathological Change

- Uninvolved/Little involvement

+ / - Variably involved

? Probable subclinical involvement

PMA Progressive Muscular Atrophy

ALS Sporadic Amyotrophic Lateral Sclerosis

ALSi Amyotrophic Lateral Sclerosis with Cognitive Impairment

ALS-FTD Motor Neurone Disease with Fronto-Temporal Dementia

MND-IBD Motor Neurone Disease-type Inclusion Body Dementia

LMN Lower Motor Neurone

UMN Upper Motor Neurone.

Pathological findings based on al Sarraj et al. 2002 Anderson et al. 1995 Iwanaga et al. 1997 Kawashima et al. 2001 Maekawa et al. 2004 Nakano 2000 Tsuchiya et al. 2002 Wilson et al. 1996 Yoshida 2004 Anderson et al. 1995 Jackson et al. 1996 Rossor et al. 2000 Bigio et al. 2003 Wilhelmsen et al. 2004 Ince et al. 2003
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