The potential relationship between neurological soft signs (NSS), akathisia, and EPS may be described by the following hypotheses:

• NSS are caused by EPS
• NSS are an integral feature of schizophrenia itself and are related to neither akathisia nor EPS
• NSS, akathisia, and EPS are frequently observed in chronic schizophrenia, and may therefore refer to a common cerebral deficit.

In the first two studies, NSS were assessed using the Heidelberg scale.  This scale comprises 16 NSS and provides a high interrater and internal reliability.  However, the Heidelberg scale1 is not restricted to motor changes but also includes some sensory NSS such as graphesthesia, the hand-face test, and two- point discrimination. As our third study was designed to investigate the potential relationship between NSS and EPS, we decided to restrict the examination of NSS to pure motor signs.

NSS are not caused by EPS
In the first two studies, all patients showed a highly significant decrease of NSS scores in the clinical course.  This decrease was more pronounced in patients with a remitting course. These findings demonstrate that NSS decrease in the course of illness with remission of psychopathological symptoms.

This decrease of NSS under antipsychotic treatment also applied to first-break, never medicated patients.  Antipsychotic therapy with benperidol for 25 days significantly decreased NSS scores.  In contrast, EPS, as measured on the Simpson and Angus scale, increased under antipsychotic treatment.

The hypothesis that NSS and EPS represent different aspects of motor changes in schizophrenia is supported by the results of other analyses.  Comparison of NSS-scores obtained in patients receiving clozapine and patients receiving conventional antipsychotics show no significant difference between the groups, although patients receiving clozapine tend to have higher NSS scores.

These findings answer the first hypothesis. NSS are not caused by EPS since they decrease with remission of the acute illness and are also observed in drug-naïve patients.

NSS are integral to schizophrenia
To address the second hypothesis, that NSS are an integral feature of schizophrenia, we investigated NSS with respect to psychopathological symptoms and antipsychotic side-effects in 81 chronic or subchronic patients.  Patients were investigated twice during a 2–3 week period.  Whereas NSS showed a significant decrease with clinical stabilization, scores for antipsychotic side-effects, as measured with the AIMS and the Simpson-Angus scale, remained almost constant.  The same applied for the mean antipsychotic dosage.  On examination one case of akathisia was present in 17 patients.  This number dropped to nine patients on the second examination.  These findings suggest that the incidence of  NSS is not correlated with antipsychotic medication.

Significant correlations were found however between NSS, BPRS anxiety/depression, anergia, thought disorders, activity and delusional ideation.  In addition, negative symptoms were significantly correlated with NSS.  Although neither the dose of antipsychotic nor scores on the AIMS and Barnes scale were significantly correlated with NSS, the score on the Simpson–Angus scale was significantly correlated with NSS.

These results partly confirm our second hypothesis:  NSS are an integral feature of schizophrenia.  With respect to akathisia and EPS, no consistent correlations were found.

Is there a common cerebral deficit?
With respect to our third hypothesis, our findings support the clinical experience that NSS and EPS tend to coincide in chronic schizophrenia.  However, prospective neuroimaging studies are needed to determine whether these motor changes are linked to a common cerebral deficit.  Recent studies conducted by the Karolinska and London groups indicate that EPS correspond to basal ganglia dysfunction.  In contrast, NSS seem to involve the motor cortex and the SMA, as demonstrated in a recent study with functional nuclear magnetic resonance imaging⁴⁷.

Summary
Our studies indicate that NSS vary in the course of illness and are significantly correlated to psychopathological symptoms.  Among the NSS, however, even motor signs do not show consistent correlations with EPS or akathisia. NSS nonetheless tend to coincide with EPS and akathisia in the chronically ill.

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