Numerous medical conditions present with acute and severe autonomic and muscular overactivity. These syndromes include Neuroleptic Malignant Syndrome, Serotonin Syndrome, Dysautonomia (or paroxysmal sympathetic storms) following acquired brain injury, Autonomic Dysreflexia, Parkinsonian-Hyperpyrexia Syndrome, Malignant Catatonia, intrathecal baclofen withdrawal, Malignant Hyperthermia, Stiff Man Syndrome and Irukandji Syndrome. In their worst forms, each of these syndromes are relatively rare, are treated by different medical specialties and show widely varying pathophysiology. Most are considered to be medical emergencies and share significant mortality rates. Previous authors have noted similarities between some of these conditions, prompting the suggestion that a single common mechanism may underlie their clinical presentation. However, the development of such an integrative model has not occurred. This paper presents a short review of the clinical syndromes, grouped by the location of pathology and mechanism of action. From this background, an integrative framework termed the excitatory:inhibitory ratio (EIR) model is presented. The EIR model consists of two inter-related networks operating at spinal and brainstem levels. The model is evaluated against pre-clinical scientific research, known pathways, each disorder's pathophysiology (where this is known) and variable severity, and used to explain the reasons behind the efficacy of current treatment regimes. Circumstantial evidence for an expanded aetiology for Malignant Hyperthermia is provided and generic treatment strategies for a number of other conditions are suggested. Finally, minor modifications to this model provide a basis to begin to explain less severe, regional "overlap" syndromes.